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Beheshti, Sayeh, and David Matthes. "The Expression Patterns of Semaphorin Genes 3b, 4a, 4f, and 6c in the Lymphoid Tissue of Mice Found Through in Situ Hybridization." Microscopy and Microanalysis 7, S2 (August 2001): 446–47. http://dx.doi.org/10.1017/s1431927600028300.
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The semaphorin family consists of a set of secreted and transmembrane proteins which contain a domain of approximately 500 amino acids called the semaphorin domain. The investigation of the role of semaphorin proteins in the nervous system has established them as chemorepellents of axons. Recent studies have identified the semaphorin proteins on the surface of cells in the immune system and in the genomes of two lytic viruses. These strongly suggest the possible involvement of the semaphorin proteins in the immune system. This study aims to understand the expression patterns of four semaphorin genes, Sema3B, Sema4A, Sema4F, and Sema6C in the lymphoid tissues of wild type mice. These proteins were chosen to represent the three subfamilies III, IV, and VI. The first family contains secreted proteins which have immunoglobulin domains (III), the second contains transmembrane proteins which have immunoglobulin domains (IV), and the third contains transmembrane proteins which do not have immunoglobulin domains (VI).
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Ha, You-Jung, Dong Woo Han, Ji Hyoun Kim, Sang Wan Chung, Eun Ha Kang, Yeong Wook Song, and Yun Jong Lee. "Circulating Semaphorin 4D as a Marker for Predicting Radiographic Progression in Patients with Rheumatoid Arthritis." Disease Markers 2018 (November 14, 2018): 1–10. http://dx.doi.org/10.1155/2018/2318386.
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Semaphorin 3A (Sema3A) and semaphorin 4D (Sema4D) are molecules which regulate immune responses as well as bone remodeling process. The aim of this study was to evaluate the serum levels of Sema3A and Sema4D and to investigate their clinical significance in rheumatoid arthritis (RA). The serum levels of Sema3A and Sema4D were measured in 130 patients with RA and 65 sex- and age-matched healthy individuals. Circulating levels of biomarkers of RA-related inflammation and bone turnover such as tumor necrosis factor- (TNF-) α, interleukin- (IL-) 6, IL-22, IL-34, osteopontin, Dkk-1, and sclerostin were also measured. Disease activity was determined by the 28-joint disease activity score (DAS28), and radiographic joint damage was assessed by the modified Sharp van der Heijde score (SHS). The serum levels of Sema3A were significantly higher in patients with RA than those in healthy controls (p<0.001), whereas serum4D levels did not differ between the two groups. The levels of Sema4D showed a positive correlation with C-reactive protein (p=0.001) and IL-6 (p<0.001) levels, whereas the levels of Sema3A showed a negative correlation with Dkk-1 (p=0.007) and TNF-α (p=0.001). Even though Sema3A and Sema4D levels were comparable between RA patients with DAS28> 3.2 and with DAS28 ≤ 3.2, RA patients with radiographic progression (ΔSHS change/year ≥ 1) had significantly higher baseline levels of Sema4D than those without progression (p=0.029). Additionally, when RA patients were divided into 3 groups using tertiles of Sema4D levels, the percentage of progressors was significantly increased (p=0.045). In multivariate logistic regression analysis, serum Sema4D levels were an independent risk factor for radiographic progression. Our results suggest that the baseline levels of Sema4D might be a useful marker to identify RA patients with subsequent radiographic progression and that Sema4D may be an active mediator involved in RA-induced joint damage.
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Miyamoto, Yuji, Fotios Loupakis, Wu Zhang, Shu Cao, Satoshi Okazaki, Martin D. Berger, Mitsukuni Suenaga, et al. "Genetic variations in semaphorin/neuropilin signaling to predict clinical outcome in patients (pts) with metastatic colorectal cancer (mCRC) receiving bevacizumab-based chemotherapy." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 11608. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.11608.
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11608 Background: Neuropilin ( NRP) is known to be an important VEGF co-receptor that acts as a key mediator of angiogenesis. Its ligands, semaphorins ( SEMA), compete with VEGF for NRP binding and can themselves have angiogenic activity. Plexins are also receptors of SEMAs, and have the GTPase activating proteins (GAPs) domain for RAS. NRPs are shown to signal through RAS pathways. We aimed to evaluate whether single nucleotide polymorphisms (SNPs) of genes involved in the SEMA/NRPpathways predict clinical outcome in bevacizumab-treated mCRC pts. Methods: Associations between nine SNPs in 7 genes ( SEMA3A, SEMA3D, SEMA3F, NRP1, NRP2, PLXNA1 and PLXND1) and clinical outcomes were evaluated in mCRC patients receiving first-line FOLFIRI-bevacizumab in a phase III trial: TRIBE ( N= 228). Associations between genotype and RAS mutation status with clinical outcomes was also examined. Main characteristics were the following: male/female = 138/90; median age = 60; RAS-wildtype/mutant = 55/116; median PFS = 9.7 months; median OS = 26.1 months, median follow-up time = 49.3 months. Results: NRP1 rs2228638 Any A ( N= 40) showed a significantly longer PFS compared to G/G variant ( N= 188) in the univariate (11.6 months (M) vs. 9.5 M, HR = 0.64, 95%CI = 0.43-0.95, p = 0.022) and the multivariate analysis (HR = 0.59, 95%CI = 0.38-0.90, p = 0.016). SEMA3F rs12632110 A/A ( N= 20) showed a significantly shorter PFS compared to any G variant (N = 205) in the multivariate analysis (HR = 1.89, 95%CI = 1.02-3.49, p = 0.043). Among RAS-mutant pts, SEMA3F rs12632110, SEMA3F rs1046956, SEMA3D rs7800072, NRP1 rs228638, PLXNA1 rs4679323 and PLXND1 rs2255703 polymorphisms were significantly associated with PFS in the univariate and multivariate analysis. PLXNA1 rs4679323 was also significantly associated with OS in the univariate and multivariate analysis. There was no association between these polymorphisms and outcome in patients with RASwildtype tumors. Conclusions: Genetic variants within SEMA/NRP pathways may be prognostic markers in RAS mutant mCRC patients treated with bevacizumab-based chemotherapy.
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Costa, C., E. Martínez-Sáez, A. Gutiérrez-Franco, H. Eixarch, Z. Castro, A. Ortega-Aznar, S. Ramón y Cajal, X. Montalban, and C. Espejo. "Expression of semaphorin 3A, semaphorin 7A and their receptors in multiple sclerosis lesions." Multiple Sclerosis Journal 21, no. 13 (October 2, 2015): 1632–43. http://dx.doi.org/10.1177/1352458515599848.
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Background: Studies in multiple sclerosis (MS) and in experimental models point to a critical role of semaphorin (sema)3A and sema7A in MS pathogenesis. Objective: The objective of this paper is to characterise the expression of sema3A, sema7A, and their receptors in MS lesions. Methods: We included 44 demyelinating lesions from MS patients, 12 lesions with acute cerebral infarct, 11 lesions with progressive multifocal leucoencephalopathy and 10 non-neurological control patients. MS lesions were classified according to inflammatory activity and all samples were immunostained for sema3A, sema7A, neuropilin 1 (Np-1), α1-integrin, and β1-integrin. Results: In MS-damaged white matter sema3A and Np-1 were both detected in microglia/macrophages, whereas reactive astrocytes expressed only sema3A. Otherwise, sema7A, α1-integrin and β1-integrin were observed in reactive astrocytes, and microglia/macrophages only expressed β1-integrin. The expression of sema3A, sema7A and their receptors is more relevant in MS than in other demyelinating diseases. Sema3A and sema7A expression correlated with the inflammatory activity of the MS lesions, suggesting their involvement in the immunological process that takes place in MS. Conclusions: The expression pattern of sema3A, sema7A and their receptors in MS lesions suggests that both molecules contribute to create a negative environment for tissue regeneration, influencing the ability to regenerate the damaged tissue.
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Williamson, Magali, Ritu Garg, and Claire M. Wells. "PlexinB1 Promotes Nuclear Translocation of the Glucocorticoid Receptor." Cells 9, no. 1 (December 18, 2019): 3. http://dx.doi.org/10.3390/cells9010003.
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Androgen receptor (AR) and glucocorticoid receptor (GR) are nuclear receptors whose function depends on their entry into the nucleus where they activate transcription of an overlapping set of genes. Both AR and GR have a role in resistance to androgen deprivation therapy (ADT), the mainstay of treatment for late stage prostate cancer. PlexinB1, a receptor for semaphorins, has been implicated in various cancers including prostate cancer and has a role in resistance to ADT. We show here that activation of PlexinB1 by Sema4D and Sema3C results in translocation of endogenous GR to the nucleus in prostate cancer cells, and that this effect is dependent on PlexinB1 expression. Sema4D/Sema3C promotes the translocation of GR-GFP to the nucleus and mutation of the nuclear localization sequence (NLS1) of GR abrogates this response. These findings implicate the importin α/β system in the Sema4D/Sema3C-mediated nuclear import of GR. Knockdown of PlexinB1 in prostate cancer cells decreases the levels of glucocorticoid-responsive gene products and antagonizes the decrease in cell motility and cell area of prostate cancer cells upon dexamethasone treatment, demonstrating the functional significance of these findings. These results show that PlexinB1 activation has a role in the trafficking and activation of the nuclear receptor GR and thus may have a role in resistance to androgen deprivation therapy in late stage prostate cancer.
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Dai, Hong, Rile Li, Michael Ittmann, Thomas M. Wheeler, and Gustavo Ayala. "796: SEMA4F Overexpression in Perineural Invasion in Vitro Model of Prostate Cancer and Its Functional Involvement in Axonogenesis." Journal of Urology 175, no. 4S (April 2006): 257–58. http://dx.doi.org/10.1016/s0022-5347(18)33032-5.
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Kigel, Boaz, Noa Rabinowicz, Asya Varshavsky, Ofra Kessler, and Gera Neufeld. "Plexin-A4 promotes tumor progression and tumor angiogenesis by enhancement of VEGF and bFGF signaling." Blood 118, no. 15 (October 13, 2011): 4285–96. http://dx.doi.org/10.1182/blood-2011-03-341388.
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Abstract Plexin-A4 is a receptor for sema6A and sema6B and associates with neuropilins to transduce signals of class-3 semaphorins. We observed that plexin-A1 and plexin-A4 are required simultaneously for transduction of inhibitory sema3A signals and that they form complexes. Unexpectedly, inhibition of plexin-A1 or plexin-A4 expression in endothelial cells using specific shRNAs resulted in prominent plexin type specific rearrangements of the actin cytoskeleton that were accompanied by inhibition of bFGF and VEGF-induced cell proliferation. The two responses were not interdependent since silencing plexin-A4 in U87MG glioblastoma cells inhibited cell proliferation and strongly inhibited the formation of tumors from these cells without affecting cytoskeletal organization. Plexin-A4 formed stable complexes with the FGFR1 and VEGFR-2 tyrosine-kinase receptors and enhanced VEGF-induced VEGFR-2 phosphorylation in endothelial cells as well as bFGF-induced cell proliferation. We also obtained evidence suggesting that some of the pro-proliferative effects of plexin-A4 are due to transduction of autocrine sema6B-induced pro-proliferative signals, since silencing sema6B expression in endothelial cells and in U87MG cells mimicked the effects of plexin-A4 silencing and also inhibited tumor formation from the U87MG cells. Our results suggest that plexin-A4 may represent a target for the development of novel anti-angiogenic and anti-tumorigenic drugs.
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Matsuoka, Ryota L., Lu O. Sun, Kei-ichi Katayama, Yutaka Yoshida, and Alex L. Kolodkin. "Sema6B, Sema6C, and Sema6D Expression and Function during Mammalian Retinal Development." PLoS ONE 8, no. 4 (April 30, 2013): e63207. http://dx.doi.org/10.1371/journal.pone.0063207.
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de Winter, F., J. C. F. Kwok, J. W. Fawcett, T. T. Vo, D. Carulli, and J. Verhaagen. "The Chemorepulsive Protein Semaphorin 3A and Perineuronal Net-Mediated Plasticity." Neural Plasticity 2016 (2016): 1–14. http://dx.doi.org/10.1155/2016/3679545.
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During postnatal development, closure of critical periods coincides with the appearance of extracellular matrix structures, called perineuronal nets (PNN), around various neuronal populations throughout the brain. The absence or presence of PNN strongly correlates with neuronal plasticity. It is not clear how PNN regulate plasticity. The repulsive axon guidance proteins Semaphorin (Sema) 3A and Sema3B are also prominently expressed in the postnatal and adult brain. In the neocortex, Sema3A accumulates in the PNN that form around parvalbumin positive inhibitory interneurons during the closure of critical periods. Sema3A interacts with high-affinity with chondroitin sulfate E, a component of PNN. The localization of Sema3A in PNN and its inhibitory effects on developing neurites are intriguing features and may clarify how PNN mediate structural neural plasticity. In the cerebellum, enhanced neuronal plasticity as a result of an enriched environment correlates with reduced Sema3A expression in PNN. Here, we first review the distribution of Sema3A and Sema3B expression in the rat brain and the biochemical interaction of Sema3A with PNN. Subsequently, we review what is known so far about functional correlates of changes in Sema3A expression in PNN. Finally, we propose a model of how Semaphorins in the PNN may influence local connectivity.
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Francks, Clyde, Simon E. Fisher, Richard K. Olson, Bruce F. Pennington, Shelley D. Smith, John C. DeFries, and Anthony P. Monaco. "Fine mapping of the chromosome 2p12-16 dyslexia susceptibility locus: quantitative association analysis and positional candidate genes SEMA4F and OTX1." Psychiatric Genetics 12, no. 1 (March 2002): 35–41. http://dx.doi.org/10.1097/00041444-200203000-00005.
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Watterston, Charlene, Rami Halabi, Sarah McFarlane, and Sarah J. Childs. "Endothelial Semaphorin 3fb regulates Vegf pathway-mediated angiogenic sprouting." PLOS Genetics 17, no. 8 (August 23, 2021): e1009769. http://dx.doi.org/10.1371/journal.pgen.1009769.
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Vessel growth integrates diverse extrinsic signals with intrinsic signaling cascades to coordinate cell migration and sprouting morphogenesis. The pro-angiogenic effects of Vascular Endothelial Growth Factor (VEGF) are carefully controlled during sprouting to generate an efficiently patterned vascular network. We identify crosstalk between VEGF signaling and that of the secreted ligand Semaphorin 3fb (Sema3fb), one of two zebrafish paralogs of mammalian Sema3F. The sema3fb gene is expressed by endothelial cells in actively sprouting vessels. Loss of sema3fb results in abnormally wide and stunted intersegmental vessel artery sprouts. Although the sprouts initiate at the correct developmental time, they have a reduced migration speed. These sprouts have persistent filopodia and abnormally spaced nuclei suggesting dysregulated control of actin assembly. sema3fb mutants show simultaneously higher expression of pro-angiogenic (VEGF receptor 2 (vegfr2) and delta-like 4 (dll4)) and anti-angiogenic (soluble VEGF receptor 1 (svegfr1)/ soluble Fms Related Receptor Tyrosine Kinase 1 (sflt1)) pathway components. We show increased phospho-ERK staining in migrating angioblasts, consistent with enhanced Vegf activity. Reducing Vegfr2 kinase activity in sema3fb mutants rescues angiogenic sprouting. Our data suggest that Sema3fb plays a critical role in promoting endothelial sprouting through modulating the VEGF signaling pathway, acting as an autocrine cue that modulates intrinsic growth factor signaling.
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Zylbersztejn, Kathleen, Maja Petkovic, Andrea Burgo, Marie Deck, Sonia Garel, Séverine Marcos, Evelyne Bloch-Gallego, et al. "The vesicular SNARE Synaptobrevin is required for Semaphorin 3A axonal repulsion." Journal of Cell Biology 196, no. 1 (January 2, 2012): 37–46. http://dx.doi.org/10.1083/jcb.201106113.
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Attractive and repulsive molecules such as Semaphorins (Sema) trigger rapid responses that control the navigation of axonal growth cones. The role of vesicular traffic in axonal guidance is still largely unknown. The exocytic vesicular soluble N-ethylmaleimide sensitive fusion protein attachment protein receptor (SNARE) Synaptobrevin 2 (Syb2) is known for mediating neurotransmitter release in mature neurons, but its potential role in axonal guidance remains elusive. Here we show that Syb2 is required for Sema3A-dependent repulsion but not Sema3C-dependent attraction in cultured neurons and in the mouse brain. Syb2 associated with Neuropilin 1 and Plexin A1, two essential components of the Sema3A receptor, via its juxtatransmembrane domain. Sema3A receptor and Syb2 colocalize in endosomal membranes. Moreover, upon Sema3A treatment, Syb2-deficient neurons failed to collapse and transport Plexin A1 to cell bodies. Reconstitution of Sema3A receptor in nonneuronal cells revealed that Sema3A further inhibited the exocytosis of Syb2. Therefore, Sema3A-mediated signaling and axonal repulsion require Syb2-dependent vesicular traffic.
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Zhou, Rongying, Yujie Mao, Lidan Xiong, and Li Li. "Integrated Transcriptome Analysis of microRNA and mRNA in Mouse Skin Derived Precursors (SKPs) and SKP Derived Fibroblast (SFBs) by RNA-Seq." Current Genomics 20, no. 1 (February 27, 2019): 49–60. http://dx.doi.org/10.2174/1389202919666181012145416.
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Background: Skin-derived precursors (SKPs) display the characteristics of self-renewal and multilineage differentiation. Objective: The study aimed to explore the molecular mechanisms of mouse SKPs differentiation into SKP-derived fibroblasts (SFBs). Methods: We compared the microRNA (miRNA) profile in mouse SKPs and SFBs by RNA sequencing. Real-time quantitative reverse transcription PCR (qRT-PCR) was performed to validate the miRNA expression. The integrated analysis of miRNA and mRNA expression data was performed to explore the potential crosstalk of miRNA-mRNA in SKP differentiation. Results: 207 differentially expressed miRNAs and 835 miRNA target genes in the gene list of integrated mRNA expression profiling were identified. Gene Ontology (GO) enrichment analysis revealed that cell differentiation and cell proliferation process were significantly enriched. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed the target genes were significantly most enriched in the cytokine-cytokine receptor interaction, cancer pathways and axon guidance signaling pathway. The most upregulated and downregulated target genes were involved in the Wnt, Notch, cytokine- cytokine receptor interaction, TGF-β, p53 and apoptotic signaling pathway. The miRNAmRNA regulatory networks and 507 miRNA-mRNA pairs were constructed. Seven miRNAs (miR- 486-3p, miR-504-5p, miR-149-3p, miR-31-5p, miR-484, miR-328-5p and miR-22-5p) and their target genes Wnt4, Dlx2, Sema4f, Kit, Kitl, Inpp5d, Igfbp3, Prdm16, Sfn, Irf6 and Clu were identified as miRNA-mRNA crosstalk pairs. Conclusion: These genes and signaling pathways might control SKPs proliferation and SKPs differentiation into SFBs during the process of SKPs differentiation, which might promote the application of SKPs in the clinical treatment of skin-related diseases by regulating SKPs proliferation and SKPs differentiation.
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Fantin, Alessandro, Charlotte H. Maden, and Christiana Ruhrberg. "Neuropilin ligands in vascular and neuronal patterning." Biochemical Society Transactions 37, no. 6 (November 19, 2009): 1228–32. http://dx.doi.org/10.1042/bst0371228.
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Blood vessels and neurons share guidance cues and cell-surface receptors to control their behaviour during embryogenesis. The transmembrane protein NRP1 (neuropilin 1) is present on both blood vessels and nerves and binds two structurally diverse ligands, the class 3 semaphorin SEMA3A and an isoform of the vascular endothelial growth factor VEGF-A termed VEGF165 (VEGF164 in mice). In vitro, SEMA3A competes with VEGF164 for binding to NRP1 to modulate the migration of endothelial cells and neuronal progenitors. It was therefore hypothesized that NRP1 signalling controls neurovascular co-patterning by integrating competing VEGF164 and SEMA3A signals. However, SEMA3A, but not VEGF164, is required for axon patterning of motor and sensory nerves, and, vice versa, VEGF164 rather than SEMA3A is required for blood vessel development. Ligand competition for NRP1 therefore does not explain neurovascular congruence. Instead, these ligands control different aspects of neurovascular patterning that have an impact on cardiovascular function. Thus SEMA3A/NRP1 signalling guides the NCC (neural crest cell) precursors of sympathetic neurons as well as their axonal projections. In addition, VEGF164 and a second class 3 semaphorin termed SEMA3C contribute to the remodelling of the embryonic pharyngeal arch arteries and primitive heart outflow tract by acting on endothelium and NCCs respectively. Consequently, loss of either of these NRP1 ligands disrupts blood flow into and out of the heart. Multiple NRP1 ligands therefore co-operate to orchestrate cardiovascular morphogenesis.
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YILDIZ, Süleyman. "Tunceli ve Çevresinden Derlenen İki Semah: Maraş Semahı Ve Kırklar Semahı." Türk Kültürü ve HACI BEKTAŞ VELİ Araştırma Dergisi 96 (December 20, 2020): 411–28. http://dx.doi.org/10.34189/hbv.96.018.
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Kim, Jung-Min, Chujiao Lin, Zheni Stavre, Matthew B. Greenblatt, and Jae-Hyuck Shim. "Osteoblast-Osteoclast Communication and Bone Homeostasis." Cells 9, no. 9 (September 10, 2020): 2073. http://dx.doi.org/10.3390/cells9092073.
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Bone remodeling is tightly regulated by a cross-talk between bone-forming osteoblasts and bone-resorbing osteoclasts. Osteoblasts and osteoclasts communicate with each other to regulate cellular behavior, survival and differentiation through direct cell-to-cell contact or through secretory proteins. A direct interaction between osteoblasts and osteoclasts allows bidirectional transduction of activation signals through EFNB2-EPHB4, FASL-FAS or SEMA3A-NRP1, regulating differentiation and survival of osteoblasts or osteoclasts. Alternatively, osteoblasts produce a range of different secretory molecules, including M-CSF, RANKL/OPG, WNT5A, and WNT16, that promote or suppress osteoclast differentiation and development. Osteoclasts also influence osteoblast formation and differentiation through secretion of soluble factors, including S1P, SEMA4D, CTHRC1 and C3. Here we review the current knowledge regarding membrane bound- and soluble factors governing cross-talk between osteoblasts and osteoclasts.
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Lu, Jian-jun, Yao-wu Su, Chao-jun Wang, Di-feng Li, and Liang Zhou. "Semaphorin 4D promotes the proliferation and metastasis of bladder cancer by activating the PI3K/AKT pathway." Tumori Journal 105, no. 3 (January 24, 2019): 231–42. http://dx.doi.org/10.1177/0300891618811280.
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The present study aimed to investigate the role of semaphorin 4D (Sema4D) in bladder cancer cell proliferation and metastasis in vivo and in vitro. Effects of Sema4D modulation on cancer cell viability and clonogenic abilities were assessed by MTT assay and colony formation assay. Cell apoptosis, cell cycle analysis, transwell assays, and wound-healing assays were also assayed. A mouse model of bladder cancer was established to observe the tumorigenesis in vivo. Our data showed that Sema4D was 4-fold upregulated in clinical bladder cancer tissues relative to noncancerous ones and differentially expressed in bladder cancer cell lines. Knockdown of Sema4D in bladder cancer T24 and 5637 cells significantly decreased cell proliferation, clonogenic potential, and motility. On the contrary, overexpression of Sema4D in bladder cancer SV-HUC-1 cells significantly increased cell viability and motility. Concordantly, knockdown of Sema4D impaired while overexpression of Sema4D promoted bladder cancer cell growth rates in xenotransplanted mice. Cell cycle was arrested by modulation of Sema4D. Cell apoptotic rates and the mitochondrial membrane potentials were consistently increased upon knockdown of Sema4D in T24 cells and 5637 cells. Western blotting revealed that epithelial–mesenchymal transition was promoted by Sema4D. The PI3K/AKT pathway was activated upon Sema4D overexpression in SV-HUC-1 cells, while it was inactivated by knockdown of Sema4D in T24 cells. All these data suggest that Sema4D promotes cell proliferation and metastasis in bladder cancer in vivo and in vitro. The oncogenic behavior of Sema4D is achieved by activating the PI3K/AKT pathway.
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Saul, D., M. Ninkovic, M. Komrakova, L. Wolff, P. Simka, T. Gasimov, B. Menger, D. B. Hoffmann, V. Rohde, and S. Sehmisch. "Effect of zileuton on osteoporotic bone and its healing, expression of bone, and brain genes in rats." Journal of Applied Physiology 124, no. 1 (January 1, 2018): 118–30. http://dx.doi.org/10.1152/japplphysiol.01126.2016.
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Estrogen deficiency and aging are associated with osteoporosis, impaired bone healing, and lower cognitive performance. Close functional and physical connections occur between bone and the central nervous system. An anti-inflammatory drug, zileuton (which is an inhibitor of arachidonate 5-lipoxygenase), is known to have a positive effect on bone tissue repair and brain ischemia. We studied the effect of zileuton on osteopenic bone and its healing and on the genes considered to be crucial for the cross talks between bone and brain. Three-month-old Sprague-Dawley rats were ovariectomized or left untreated. After 8 wk, bilateral metaphyseal tibia osteotomy with plate osteosynthesis was performed in all rats. Ovariectomized rats were fed with food containing zileuton (1, 10, or 100 mg/kg body wt) for 5 wk. In tibiae, bone volume, callus and cortical volume, and gene expression of osteocalcin and alkaline phosphatase were enhanced by zileuton (10 or 100 mg); biomechanical properties and bone density were not changed. In femur, zileuton enlarged cortical volume distal and trabecular volume proximal, decreasing their density. The expression level of brain Sema3a, known to regulate bone mass positively, was downregulated after ovariectomy. In contrast, bone Sema4d, a negative regulator of bone mass, was upregulated in the tibia callus after ovariectomy, whereas zileuton treatment (10 or 100 mg) resulted in reverse effects. Here, we describe for the first time the expression of Rbbp4 mRNA and its increase in tibia after ovariectomy. Zileuton caused downregulation of Rbbp4 in the hippocampus and had an effect on bone healing, changed the expression of genes involved in cross talk between bones and brain, and may be a potent drug for further examination in estrogen deficiency-related dysfunction(s). NEW & NOTEWORTHY Zileuton, a 5-lipoxygenase inhibitor, increased bone volume, callus and cortical volume in osteotomized tibia, and trabecular and cortical volume in femur. Although the expression of Sema3a (positively regulating bone mass) in brain was downregulated and Sema4d (negatively regulating bone mass) was upregulated in tibia callus after ovariectomy, zileuton could counteract these effects. Rbbp4 (involved in age-related memory loss) was increased in tibia callus after ovariectomy.
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Nishide, Masayuki, Satoshi Nojima, Daisuke Ito, Hyota Takamatsu, Shohei Koyama, Sujin Kang, Tetsuya Kimura, et al. "Semaphorin 4D inhibits neutrophil activation and is involved in the pathogenesis of neutrophil-mediated autoimmune vasculitis." Annals of the Rheumatic Diseases 76, no. 8 (April 17, 2017): 1440–48. http://dx.doi.org/10.1136/annrheumdis-2016-210706.
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ObjectivesInappropriate activation of neutrophils plays a pathological role in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The aim of this study was to investigate the functions of semaphorin 4D (SEMA4D) in regulation of neutrophil activation, and its involvement in AAV pathogenesis.MethodsSerum levels of soluble SEMA4D were evaluated by ELISA. Blood cell-surface expression of membrane SEMA4D was evaluated by flow cytometry. To determine the functional interactions between neutrophil membrane SEMA4D and endothelial plexin B2, wild-type and SEMA4D−/− mice neutrophils were cultured with an endothelial cell line (MS1) stained with SYTOX green, and subjected to neutrophil extracellular trap (NET) formation assays. The efficacy of treating human neutrophils with recombinant plexin B2 was assessed by measuring the kinetic oxidative burst and NET formation assays.ResultsSerum levels of soluble SEMA4D were elevated in patients with AAV and correlated with disease activity scores. Cell-surface expression of SEMA4D was downregulated in neutrophils from patients with AAV, a consequence of proteolytic cleavage of membrane SEMA4D. Soluble SEMA4D exerted pro-inflammatory effects on endothelial cells. Membranous SEMA4D on neutrophils bound to plexin B2 on endothelial cells, and this interaction decreased NET formation. Recombinant plexin B2 suppressed neutrophil Rac1 activation through SEMA4D’s intracellular domain, and inhibited pathogen-induced or ANCA-induced oxidative burst and NET formation.ConclusionsNeutrophil surface SEMA4D functions as a negative regulator of neutrophil activation. Proteolytic cleavage of SEMA4D as observed in patients with AAV may amplify neutrophil-mediated inflammatory responses. SEMA4D is a promising biomarker and potential therapeutic target for AAV.
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Yoshimura, Hideaki, Yukie Tsubokura, Masaaki Hotta, Atsushi Satake, Tomoki Ito, Atsushi Kumanogoh, and Shosaku Nomura. "A Critical Role of Host-Derived Semaphorin-4A for Regulating T Cell Immune Responses in Acute Graft Versus Host Disease." Blood 132, Supplement 1 (November 29, 2018): 3322. http://dx.doi.org/10.1182/blood-2018-99-113853.
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Abstract Semaphorins, originally identified as repulsive axon-guidance factors that participate in neuronal development. Several semaphorins are involved in various phases of immune responses, as has been shown recently. Semaphorin4A (Sema4A), a class IV transmembrane semaphorin, is preferentially expressed in dendritic cells (DCs) and Th1 cells. Previous studies suggested that Sema4A is involved in Ag-specific T cell priming, and in Th1 cell and Th17 cell differentiation. Additionally, Sema4A is required for the stability and function of Tregs. However, the role of Sema4A in alloimmune responses remains to be elucidated. In this study, we examined the contribution of Sema4A to T cell immune responses in the context of allogeneic hematopoietic stem cell transplantation (allo-HCT). To test the role of Sema4A in T cell proliferation, we performed in vitro T cell proliferation assay using dendritic cells harvested from wild-type or Sema4A-KO mice. Conventional CD4+T cells cocultured with DCs harvested from wild-type and Sema4A-KO mice proliferated equally in the presence of anti-CD3 antibody. In contrast, anti-CD3-induced proliferation of Tregs cocultured with DCs harvested from Sema4A-KO mice was attenuated compared to Tregs cocultured with DCs harvested from wild-type mice, suggesting that Sema4A is required for maximum proliferation of Tregs. We next investigated the effects of Sema4A deficiency in acute GVHD. We employed a murine acute GVHD model (B6→BALB/c) and monitored every day for survival. Body weight was assessed 2-3 times per week. First, to investigate the role of host Sema4A, lethally irradiated wild-type and Sema4A-KO mice were injected with T cell-depleted bone marrow cells and T cells isolated from wild-type B6. Sema4A-KO host mice developed significantly higher mortality compared to wild-type host mice (p<0.001) (Figure). On day 7 after allo-HCT, the proportion of Tregs in the spleen were significantly decreased in Sema4A-KO host mice compared to wild-type host mice (p<0.05). Both donor-derived preexisting natural Tregs and inducible Tregs in Sema4A-KO host mice were significantly decreased compared to wild-type host mice, although relatively less in inducible Tregs. We investigated the production of proinflammatory cytokines (IFN-g, IL-17, IL-4 and IL-13) of T cells in the spleen by intracellular cytokine staining. The proportion of IL-17+CD4+ T cells in Sema4A-KO host was slightly but not significantly decreased compared to wild-type host, whereas similar proportion of IFN-g+CD4+T cells was observed in Sema4A-KO and wild-type host mice. In contrast, the proportion of IL-4+CD4+ T cells in Sema4A-KO host was significantly increased in Sema4A-KO host mice compared to wild-type host mice, suggesting Sema4A deficiency skewed cytokine polarization of T cells after allo-HCT. Subsequently, we used Sema4A-KO and wild-type B6 mice donor to investigate the role of donor-derived Sema4A. Host mice transplanted from Sema4A-KO donor developed comparable mortality with host mice transplanted with wild-type donor, suggesting that donor-derived Sema4A does not play an important role in controlling graft versus host reactions in this model. Together, these results suggest that Sema4A contributes to Treg maintenance and the regulation of T cell responses after allo-HCT, which may have clinical implications for the novel approach in the treatment and protection of GVHD. Figure. Figure. Disclosures Ito: Bristol-Myers Squibb: Honoraria, Research Funding; Takeda: Honoraria; Novartis Pharma: Honoraria; Pfizer: Honoraria; Mundipharma: Honoraria; Celgene: Honoraria.
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Zhu, Li, Tao Wang, Hong Jiang, Timothy J. Stalker, Karen P. Fong, Peter J. Gruber, and Lawrence F. Brass. "Deletion of the Semaphorin, Sema4D, but Not Inhibition of Sema4D Shedding by ADAM17, Impairs Platelet Function and Reduces Infarct Size After Myocardial Ischemia." Blood 114, no. 22 (November 20, 2009): 771. http://dx.doi.org/10.1182/blood.v114.22.771.771.
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Abstract Abstract 771 Introduction. Platelets are activated early during the reperfusion of ischemic myocardium, potentially exacerbating the extent of ischemia/reperfusion (I/R) injury. We have recently shown (Zhu, et al., PNAS 2007) that platelets express the semaphorin family member, sema4D, as do T-cells. Sema4D is a cell surface protein whose receptors are expressed by B-cells, monocytes and endothelial cells as well as platelets. Loss of sema4D expression in mice causes a defect in signaling downstream of the platelet collagen receptor, glycoprotein (GP) VI, inhibiting platelet function in vitro and in vivo, and reducing the extent of platelet hyperresponsiveness and atherothrombosis in the setting of dyslipidemia (Zhu, et al. ATVB 2009). Because of the role played by platelets, leukocytes and endothelial cells in reperfusion injury, here we asked whether loss of sema4D expression can also protect the heart, reducing the extent of damage following temporary ischemia. Methods. The left anterior descending coronary artery of anaesthetized mice was ligated for 45 min. After reperfusion for 48 hours, the mice were re-anesthetized and perfused with 2,3,5-triphenyltetrazolium chloride to measure the area of infarction. Fluorescent microspheres were used to delineate the area at risk. Comparisons were made between sema4D(−/−) and wild type mice produced by breeding sema4D(+/−) heterozygotes. Results. Although there was no difference between the sema4D(−/−) and WT mice with respect to either heart size or area at risk, we observed a substantial (57%) decrease in infarct size in the sema4D(−/−) mice expressed as a fraction of the area at risk (N=7-9, p<0.005). Since sema4D is shed from the surface of activated platelets and T-cells by the metalloprotease, ADAM17, producing a large bioactive fragment, we next asked whether the protection against ischemia/reperfusion injury conferred by the sema4D knockout is due to the loss of cell-associated or soluble sema4D. Chimeric mice were produced in which hematopoiesis was reconstituted in irradiated sema4D(+/+) mice using fetal liver cells from mouse embryos that lack functional ADAM17. This produces mice in which sema4D is expressed as usual in the hematopoietic lineages, but unable to be shed. Chimerism, inhibition of sema4D shedding and recovery of normal cell counts were confirmed after transplantation. The ischemia/reperfusion studies were repeated comparing chimeras reconstituted with ADAM17-deficient and ADAM17-replete fetal liver cells. In contrast to the sema4D knockout, the extent of infarction was the same whether or not ADAM17 was functional and sema4D was shed. Conclusions. Although the role of sema4D and its receptors have been studied most extensively in the context of T-cell interactions with B-cells, our previous studies have made a case for the involvement of sema4D in platelet:platelet and platelet:endothelial cell interactions. We now show for the first time that 1) loss of sema4D expression in mice confers protection against ischemia/reperfusion injury in the myocardium, and 2) preventing the formation of soluble, bioactive sema4D is insufficient to recapitulate this effect. Since sema4D and its receptors are expressed on more than just platelets, it cannot be concluded that the observed protection in the knockout is solely due to the absence of platelet sema4D. However, experience with other knockouts that reduce platelet function suggests that the defects that we have observed in sema4D(−/−) platelet function are likely to contribute. Regardless of whether expression on platelets is entirely or only partly responsible for the observed phenotype, sema4D is an interesting target for therapeutic intervention. Disclosures: No relevant conflicts of interest to declare.
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Wannemacher, Kenneth M., Li Zhu, Hong Jiang, Karen P. Fong, Timothy J. Stalker, Dooyoung Lee, Anh N. Tran, et al. "Diminished contact-dependent reinforcement of Syk activation underlies impaired thrombus growth in mice lacking Semaphorin 4D." Blood 116, no. 25 (December 16, 2010): 5707–15. http://dx.doi.org/10.1182/blood-2010-04-279943.
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Abstract We recently reported that Semaphorin 4D (Sema4D) and its receptors are expressed on the platelet surface and showed that Sema4D(−/−) mice have a selective defect in collagen-induced platelet aggregation and an impaired vascular injury response. Here we investigated the mechanisms involved, tested the role of platelet-platelet contacts in Sema4D-mediated events, and examined the relationship between Sema4D-dependent signaling and integrin αIIbβ3 outside-in signaling. The results show that spleen tyrosine kinase (Syk) activation, an early step in collagen signaling via the glycoprotein VI (GPVI)/FcRγ complex, is greatly reduced in Sema4D(−/−) platelets and can be restored by adding soluble Sema4D. Earlier events, including FcRγ phosphorylation, occur normally; later events are impaired. In contrast, when engagement of αIIbβ3 was blocked, Sema4D(−/−) and control platelets were indistinguishable in assays of Syk activation, adhesion, spreading on collagen, and activation of αIIbβ3. Finally, we found that, unlike the Sema4D knockout, αIIbβ3 blockade inhibited FcRγ phosphorylation and that stimulating aggregation with Mn2+ failed to normalize Syk activation in the absence of Sema4D. Collectively, these results show that αIIbβ3 and Sema4D jointly promote collagen responses by amplifying Syk activation, partly by forming integrin-mediated contacts that enable the binding of Sema4D to its receptors and partly through integrin outside-in signaling. These 2 processes are interdependent, but distinguishable.
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Lei, Jinlai, Yahui Fu, Yan Zhuang, and Kun Zhang. "Sema4D Aggravated LPS-Induced Injury via Activation of the MAPK Signaling Pathway in ATDC5 Chondrocytes." BioMed Research International 2020 (April 25, 2020): 1–11. http://dx.doi.org/10.1155/2020/8691534.
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Osteoarthritis (OA) is the most common chronic degenerative joint disease, and it remains the main cause of chronic disability in elderly individuals. Sema4D (semaphorin 4D) is involved in the immune system and related to bone injury, osteoporosis, osteoblast differentiation, and rheumatoid arthritis. However, the role of Sema4D in OA remains unclear. Hence, the LPS-stimulated chondrocyte cell injury model was constructed in this study to investigate the role of Sema4D in OA development. The results showed that Sema4D was increased in LPS-treated ATDC5 cells, and the knockdown of Sema4D suppressed the decline of cell viability, the increase of cell apoptosis, and the increase of IL-6, IL-1β, and TNF-α secretion in ATDC5 cells induced by LPS. Meanwhile, Sema4D overexpression aggravated the cell injury triggered by LPS, and inhibiting Plexin B1 partly abolished the effect of Sema4D overexpression on LPS-induced chondrocyte injury. Furthermore, silencing of Sema4D blocked the activation of the MAPK pathway in LPS-stimulated ATDC5 cells. Enhanced Sema4D promoted the activation of the MAPK pathway in LPS-stimulated ATDC5 cells. What is more, inhibiting the MAPK signaling pathway abolished the promoting effect of Sema4D overexpression on LPS-induced chondrocyte injury. Therefore, our study suggested that the knockdown of Sema4D protects ATDC5 cells against LPS-induced injury through inactivation of the MAPK signaling pathway via interacting with Plexin B1.
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Iyer, Apoorva, and Svetlana Chapoval. "Neuroimmune Semaphorin 4A in Cancer Angiogenesis and Inflammation: A Promoter or a Suppressor?" International Journal of Molecular Sciences 20, no. 1 (December 30, 2018): 124. http://dx.doi.org/10.3390/ijms20010124.
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Neuroimmune semaphorin 4A (Sema4A), a member of semaphorin family of transmembrane and secreted proteins, is an important regulator of neuronal and immune functions. In the nervous system, Sema4A primarily regulates the functional activity of neurons serving as an axon guidance molecule. In the immune system, Sema4A regulates immune cell activation and function, instructing a fine tuning of the immune response. Recent studies have shown a dysregulation of Sema4A expression in several types of cancer such as hepatocellular carcinoma, colorectal, and breast cancers. Cancers have been associated with abnormal angiogenesis. The function of Sema4A in angiogenesis and cancer is not defined. Recent studies have demonstrated Sema4A expression and function in endothelial cells. However, the results of these studies are controversial as they report either pro- or anti-angiogenic Sema4A effects depending on the experimental settings. In this mini-review, we discuss these findings as well as our data on Sema4A regulation of inflammation and angiogenesis, which both are important pathologic processes underlining tumorigenesis and tumor metastasis. Understanding the role of Sema4A in those processes may guide the development of improved therapeutic treatments for cancer.
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Suvannasankha, Attaya, Colin D. Crean, Douglas R. Tompkins, Jesus Delgado-Calle, Teresita M. Bellido, G. David Roodman, and John M. Chirgwin. "Regulation of Osteoblast Function in Myeloma Bone Disease By Semaphorin 4D." Blood 128, no. 22 (December 2, 2016): 4439. http://dx.doi.org/10.1182/blood.v128.22.4439.4439.
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Abstract Multiple myeloma (MM) bone disease (MMBD) is characterized by activation of osteoclasts and suppression of osteoblastic differentiation, with these changes in the bone microenvironment supporting MM cell growth and drug resistance. These complex interactions between MM cells and bone cells are incompletely understood. Current bone targeted therapy with bisphosphonates or Denosumab only blocks bone resorption but has no effect on osteoblast activity and only modest effects on MM growth. Therefore, new MMBD treatments are needed. Semaphorin-4D (Sema4D; CD100), is made by osteoclasts and inhibits osteoblasts by binding to the Plexin B receptor. Breast cancers also express Sema4d, and silencing sema4D in MDA-MB-231 breast cancer cells suppresses bone metastasis (Yang Y et al, PLoS One 2016). Since breast cancers and MM both cause osteolytic bone destruction and soluble Sema4D and Plexin B levels are increased in sera of MM patients (Terpos et al, 2012), we tested if sema4D contributed to MMBD. qPCR analysis of human MM cell lines and primary CD138+ cells showed MM cells express high levels of sema4D mRNA, comparing to the MDA-MB-231 breast cancer cells. Analysis of previously reported gene expression array data confirmed that MM cells express sema4D at a higher level compared to bone marrow plasma cells of MGUS and healthy donors (GenomicScape.com; Zhan F et al, Blood 2007; Mattiolo M et al, Oncogene, 2005). These results plus those of Terpos et al suggest that MM cells commonly express Sema4D. We next asked if the bone microenvironment increases MM expression of Sema4D. We co-cultured human MM cell lines RPMI8226 and JJN3 with mouse bones. Species -specific changes in tumor and bone were evaluated by quantitative RT-PCR. MM cells engrafted onto mouse bones, increasing markers of osteolysis similar to those seen in MM bone disease. After a week of co-culture, Sema4D expression was increased in MM cells (mean ±SD; 4.2±0.4; p=0.023), compared to MM cells grown alone. In addition, bones co-cultured with MM cells expressed higher Sema4D mRNA than bones alone (mean ±SD; 3.6±0.21; p=0.03). While co-culture increased both MM and bone Sema4D, markers of osteoblast activity, Col1a1, alkaline phosphatase and osteocalcin were suppressed. Preliminary experiments suggest that osteocytes are a major source of Sema4D expression in bone, in addition to active osteoclasts, which are much rarer cells than osteocytes. The induction of Sema4D in bone was only partially inhibited by 100nM zoledronic acid to inhibit osteoclast activity. Since osteocytes can physically interact with MM cells in vivo (Delgado Calle, Cancer Res 2016), we then tested the effect of MM cells on osteocyte sema4D expression in co-cultures of RPMI 8226 and JJN3 MM cells with MOL-Y4 osteocytic cells, separated by transwells. Both MM cell lines increased the Sema4D mRNA content of MLO-Y4 cells (mean ±SD; 3.1±0.4; p=0.036), suggesting that myeloma-secreted factors regulate osteocyte Sema4D expression. Since Sema4D is a potent osteoblast inhibitor, our data suggest that osteocyte -derived Sema4D may be a major contributor to MMBD, and that neutralization of Sema4D activity should improve the suppressed bone formation in MM. Disclosures Roodman: Amgen: Consultancy.
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Ruffolo, Luis I., Nicholas A. Ullman, Benjamin Dale, Katherine M. Jackson, Paul Burchard, Mary Georger, Rachel Jewell, et al. "Antibody blockade of semaphorin 4D to sensitize pancreatic cancer to immune checkpoint blockade." Journal of Clinical Oncology 38, no. 5_suppl (February 10, 2020): 26. http://dx.doi.org/10.1200/jco.2020.38.5_suppl.26.
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26 Background: Pancreatic ductal adenocarcinoma (PDAC) carries a dismal prognosis, and will soon become the second leading cause of cancer mortality. Unfortunately, T-cell directed immunotherapies have failed to demonstrate efficacy in PDAC. These failures may in part be mediated by an immunosuppressive tumor microenvironment (TME). Semaphorin 4D (Sema4D) is a glycoprotein which binds its cognate receptors Plexin B1/B2. Here we present our work in blocking Sema4D in a murine model of PDAC. Methods: C57b/6 mice were orthotopically injected with PDAC line (KP2) derived from KRASG12D,TP53Flox/Wt;P48-Cre autochthonous tumors and confirmed for disease by ultrasound. Mice were treated with FOLFIRINOX (5-FU, Irinotecan, Oxaliplatin, weekly), immune checkpoint blockade (ICB) (anti-PD1, anti-CTLA-4 mAbs bi-weekly), and anti-Sema4D mAB (bi-weekly). Human and mouse circulating and tumor infiltrating leukocytes were interrogated through flow cytometry (FACS) for immune subset and expression of Sema4D and Plexin receptors. Archived human PDAC tissues were assessed through quantitative immunohistochemistry (IHC) for presence of Sema4D positive infiltrate. Results: Both FACS and IHC analysis of human PDAC specimens confirm the presence and increased prevalence over normal pancreata of Sema4D lymphocytes and Plexin B1/B2 expressing tumor associated macrophages (TAMs). KP2 orthotopically injected mice exhibited longer survival when treated with the triple combination of FOLFIRINOX, ICB, and anti-Sema4D antibody, compared to FOLFIRINOX alone, FOLFIRINOX plus ICB, or FOLFIRINOX plus anti-Sema4D antibody (P < 0.02). Flow cytometric analysis of anti-Sema4D and ICB treated murine tumors show a doubling of penetration by CD 8+ effector T cells within tumors compared to control groups (P = 0.03). A loss in Sema4D fluorescence signal via FACS in tumor-infiltrating CD3+ leukocytes was observed in mice treated with anti-SEMA4D, confirming penetration and target blockade within the TME. Conclusions: Sema4D and Plexin B1/B2 leukocytes penetrate human PDAC tumors, and treatment with Sema4D blocking antibody improved response to ICB in combination with standard of care FOLFIRINOX in preclinical murine studies.
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Yukawa, Kazunori, Tetsuji Tanaka, Noriko Takeuchi, Hiroyuki Iso, Li Li, Akira Kohsaka, Hidefumi Waki, et al. "Sema4D/CD100 Deficiency Leads to Superior Performance in Mouse Motor Behavior." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 36, no. 03 (May 2009): 349–55. http://dx.doi.org/10.1017/s0317167100007101.
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Background:Sema4D/CD100 is a type of class 4 semaphorin, exhibiting crucial rôles in growth cone guidance in developing neurons. Sema4D is widely expressed throughout the central nervous system in embryonic mouse brain, and is selectively localized to oligodendrocytes and myelin in the postnatal brain. However, direct evidence of the actual involvement of Sema4D in the neuronal network development crucial for neurobehavioral performance is still lacking. The present study therefore examined whether Sema4D deficiency leads to abnormal behavioral development.Methods:Both wild-type and Sema4D-deficient mice were subjected to behavioral analyses including open-field, adhesive tape removal, rotarod tests and a water maze task.Results:Open-field tests revealed increased locomotor activity in Sema4D-deficient mice with less percentage of time spent in the center of the field. In both the adhesive tape removal and rotarod tests, which examine motor coordination and balance, Sema4D-deficient mice showed significantly superior performance, suggesting facilitated motor behavior. Both Sema4D-deficient and wild-type mice successfully learnt the water maze task, locating a hidden escape platform, and also showed precise memory for the platform position in probe tests. However, the swimming speed of Sema4D-deficient mice was significantly faster than that of wild-type mice, providing further evidence of their accelerated motor behavior.Conclusion:Our mouse behavioral analyses revealed enhanced motor activity in Sema4D-deficient mice, suggesting the crucial involvement of Sema4D in the neurodevelopmental processes of the central structures mediating motor behavior in mice.
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Mao, Yilin, Elizabeth Evans, Vikas Mishra, Leslie Balch, Allison Eberhardt, Maurice Zauderer, and Wendy Gold. "Anti-Semaphorin 4D Rescues Motor, Cognitive, and Respiratory Phenotypes in a Rett Syndrome Mouse Model." International Journal of Molecular Sciences 22, no. 17 (August 31, 2021): 9465. http://dx.doi.org/10.3390/ijms22179465.
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Rett syndrome is a neurodevelopmental disorder caused by mutations of the methyl-CpG binding protein 2 gene. Abnormal physiological functions of glial cells contribute to pathogenesis of Rett syndrome. Semaphorin 4D (SEMA4D) regulates processes central to neuroinflammation and neurodegeneration including cytoskeletal structures required for process extension, communication, and migration of glial cells. Blocking SEMA4D-induced gliosis may preserve normal glial and neuronal function and rescue neurological dysfunction in Rett syndrome. We evaluated the pre-clinical therapeutic efficacy of an anti-SEMA4D monoclonal antibody in the Rett syndrome Mecp2T158A transgenic mouse model and investigated the contribution of glial cells as a proposed mechanism of action in treated mice and in primary glial cultures isolated from Mecp2T158A/y mutant mice. SEMA4D is upregulated in neurons while glial fibrillary acidic protein and ionized calcium binding adaptor molecule 1-positive cells are upregulated in Mecp2T158A/y mice. Anti-SEMA4D treatment ameliorates Rett syndrome-specific symptoms and improves behavioural functions in both pre-symptomatic and symptomatic cohorts of hemizygous Mecp2T158A/y male mice. Anti-SEMA4D also reduces astrocyte and microglia activation in vivo. In vitro experiments demonstrate an abnormal cytoskeletal structure in mutant astrocytes in the presence of SEMA4D, while anti-SEMA4D antibody treatment blocks SEMA4D–Plexin B1 signaling and mitigates these abnormalities. These results suggest that anti-SEMA4D immunotherapy may be an effective treatment option to alleviate symptoms and improve cognitive and motor function in Rett syndrome.
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Sun, Tianliang, Lida Yang, Harmandeep Kaur, Jenny Pestel, Mario Looso, Hendrik Nolte, Cornelius Krasel, et al. "A reverse signaling pathway downstream of Sema4A controls cell migration via Scrib." Journal of Cell Biology 216, no. 1 (December 22, 2016): 199–215. http://dx.doi.org/10.1083/jcb.201602002.
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Semaphorins comprise a large family of ligands that regulate key cellular functions through their receptors, plexins. In this study, we show that the transmembrane semaphorin 4A (Sema4A) can also function as a receptor, rather than a ligand, and transduce signals triggered by the binding of Plexin-B1 through reverse signaling. Functionally, reverse Sema4A signaling regulates the migration of various cancer cells as well as dendritic cells. By combining mass spectrometry analysis with small interfering RNA screening, we identify the polarity protein Scrib as a downstream effector of Sema4A. We further show that binding of Plexin-B1 to Sema4A promotes the interaction of Sema4A with Scrib, thereby removing Scrib from its complex with the Rac/Cdc42 exchange factor βPIX and decreasing the activity of the small guanosine triphosphatase Rac1 and Cdc42. Our data unravel a role for Plexin-B1 as a ligand and Sema4A as a receptor and characterize a reverse signaling pathway downstream of Sema4A, which controls cell migration.
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Dziobek, Konrad, Marcin Opławski, Beniamin Grabarek, Nikola Zmarzły, Robert Kiełbasiński, Ewa Leśniak, Piotr Januszyk, et al. "Changes in Expression Pattern of SEMA3F Depending on Endometrial Cancer Grade - Pilot Study." Current Pharmaceutical Biotechnology 20, no. 9 (September 6, 2019): 727–32. http://dx.doi.org/10.2174/1389201020666190619145655.
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Background: In the course of neoplastic diseases, a reduction in SEMA3F expression is observed, which translates into an increase in the proliferative and proangiogenic potential of cells forming the tumor and the surrounding microenvironment. Objective: The aim of this study was to determine the changes in SEMA3F level in endometrial cancer depending on its grade. Methods: The study material consisted of tissue samples: 15 without neoplastic changes (control group) and 45 with endometrial cancer (G1, 17; G2, 15; G3, 13; study group). SEMA3F expression was assessed using the immune-histochemical method. Results: The expression of SEMA3F was observed in the control group (Me = 159.38) and in the study group (G1, Me = 121.32; G2, Me = 0; G3, Me = 130.37). Differences between each grade and control and between individual grades were statistically significant. There were no significant correlations between SEMA3F expression and weight and Body Mass Index (BMI). The reduced SEMA3F expression in tumor tissue compared to healthy tissue indicates that this protein plays key roles in proliferation and angiogenesis. Conclusion: We found that depending on the severity of the disease, cancer adopts different survival strategies, where SEMA3F plays an important role. As a molecular marker, SEMA3F is not sensitive to weight and BMI.
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Mou, Peipei, Zhao Zeng, Qiang Li, Xiaohui Liu, Xiaoran Xin, Kenneth M. Wannemacher, Changgeng Ruan, Renhao Li, Lawrence F. Brass, and Li Zhu. "Identification of a calmodulin-binding domain in Sema4D that regulates its exodomain shedding in platelets." Blood 121, no. 20 (May 16, 2013): 4221–30. http://dx.doi.org/10.1182/blood-2012-11-470609.
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Key Points This study identifies a calmodulin-binding sequence in Sema4D and shows that calmodulin binds to Sema4D in resting platelets. Dissociation of the Sema4D:calmodulin complex is sufficient to trigger Sema4D cleavage and shedding of the extracellular domain.
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Mou, Peipei, Zhao Zeng, Lijie Ren, Qiang Li, Kenneth M. Wannemacher, Xi Mo, Lawrence F. Brass, and Li Zhu. "Identification of a Region within the Cytoplasmic Domain of Sema4D That Binds Calmodulin and Regulates Shedding of the Sema4D Exodomain in Platelets,." Blood 118, no. 21 (November 18, 2011): 3249. http://dx.doi.org/10.1182/blood.v118.21.3249.3249.
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Abstract Abstract 3249 We have previously shown that the 150 kDa semaphorin family member, Sema4D (or CD100), is expressed on the surface of human and mouse platelets, where it is able to selectively reinforce collagen-initiated platelet activation by engaging receptors in trans on adjoining platelets in a contact-dependent manner. Key to this effect is the Sema4D extracellular domain, which in addition to being a ligand for Sema4D receptors, is a substrate for the metalloprotease, ADAM17 in platelets. Our previous studies suggest that ADAM17 cleaves Sema4D and other platelet surface proteins close to the platelet plasma membrane gradually producing, in the case of Sema4D, a single large (≈120 kDa) exodomain fragment and a smaller (≈28 kDa) fragment that includes the transmembrane domain and the cytoplasmic domain and remains associated with the platelet (Zhu, et al., PNAS 2007). Exodomain shedding in platelets can be triggered by the phorbol ester, PMA, and by physiologic agonists such as thrombin that raise the cytoplasmic Ca++ concentration, but the mechanisms that regulate the shedding of Sema4D have not been defined. Here we have studied the potential role of an interaction between calmodulin and the Sema4D cytoplasmic domain. Using a public resource (http://calcium.uhnres.utoronto.ca/ctdb/ctdb/home.html), we identified a potential calmodulin-binding sequence (GYLPRQCLKFRSALLIGKKKPKS-COOH, Gly758–Ser780) within the membrane-proximal region of the Sema4D cytoplasmic domain. To test whether this region binds calmodulin, a 23 amino acid peptide corresponding to the predicted Sema4D calmodulin binding sequence (SCBP) was synthesized, as was a scrambled control peptide (RLIKACRQPKPKYKLLGFGSSKL or scrambled SCBP), which is not predicted to bind calmodulin. The results show that SCBP, but not scrambled SCBP, was able to bind to calmodulin-agarose and retrieve calmodulin from platelet lysates. As constitutive association of calmodulin with glycoprotein (GP) Ib has been shown prevent ADAM17-dependent GPIb alpha shedding in platelets, we incubated human platelets with the calmodulin inhibitor, W7. The inhibitor induced gradual Sema4D shedding that was detectable after 5 min and reached a maximum at 60 min, kinetics that are similar to those we have observed with platelet agonists. However, in contrast to platelet agonists, W7-induced Sema4D shedding generated a smaller retained fragment (≈24 kDa Vs. 28 kDa) suggesting that there is either a second or different site of cleavage. Despite their polybasic sequences, flow cytometry and confocal microscopy showed that FITC-conjugated SCBP and scrambled-SCBP are able to cross the plasma membrane. Addition of SCBP, but not scrambled-SCBP, to platelet caused cleavage of Sema4D, producing the same 28 kDa fragment observed with thrombin and PMA. In all cases cleavage of Sema4D was blocked by the metalloprotease inhibitor, TAPI-2. Combined with our earlier observations, these results suggest that 1) Sema4D is a calmodulin binding protein with a site of interaction in the membrane-proximal cytoplasmic domain and a site of cleavage by ADAM17 in the membrane-proximal exodomain, 2) the detachment of calmodulin from Sema4D may be the trigger for Sema4D cleavage in response to platelet agonists, and 3) in contrast to W7, decoying calmodulin from binding sites on Sema4D and other metalloprotease substrates on the platelet surface, as we have done here with a Sema4D cytoplasmic domain peptide, may trigger the same events seen in activated platelets and provide a tool to understand the underlying mechanisms. Disclosures: No relevant conflicts of interest to declare.
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Jin, Zhe, Mary D. Chau, and Zheng-Zheng Bao. "Sema3D,Sema3F, andSema5Aare expressed in overlapping and distinct patterns in chick embryonic heart." Developmental Dynamics 235, no. 1 (January 2006): 163–69. http://dx.doi.org/10.1002/dvdy.20614.
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Lontos, Konstantinos, Juraj Adamik, Peng Zhang, Quanhong Sun, David Roodman, Attaya Suvannasankha, and Deborah Lynn Galson. "Semaphorin 4D to suppress bone formation in multiple myeloma." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 8039. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.8039.
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8039 Background: Myeloma bone disease is characterized by osteoclast activation and long-term osteoblast suppression. We investigated if Semaphorin 4D (Sema4D; CD100) plays a role in these processes. Sema4D has been shown to be a potent osteoblast inhibitor (Negishi-Koga T et al, Nat Med. 2011). A study recently identified that the breast cancer cell line MDA-MB-231 utilizes Sema4D to create osteolysis (Yang Y et al, PLOS One 2016). There have been previous data that Sema4D is increased in the serum of myeloma patients (Terpos et al, Blood 2012) and that co-culturing myeloma cell lines with osteocytes increases the expression of Sema4D mRNA in both (Suvannasankha et al, Blood 2016). We sought to investigate if myeloma cells are using Sema4D to suppress bone formation and if they affect the levels of Sema4D produced by osteoclasts. Methods: We used lentivirus carrying shRNA for Sema4D or control (Scr) to knock down the level of the protein in the 5TGM1 murine myeloma cell line. Knockdown was verified by qPCR and Western Blot. We subsequently co-cultured the 5TGM1 cells with the MC3T3-subclone M4 (MC4) murine stromal cell line for 2 days, removed the myeloma cells and then differentiated the MC4 cells using ascorbic acid and β-glycerolphosphate. At day 5, we analyzed the cells for Runx2 (a critical gene for the differentiation of stromal cells into osteoblasts) expression utilizing qPCR. Also, we performed qPCR in primary osteoclast (OCL) mouse cells differentiating into OCL with RANKL with or without pre-treatment with myeloma-conditioned media for 3 days before the addition of RANKL. Results: When 5TGM1-Scr were co-cultured with MC4 cells the expression of Runx2 on day 5 was decreased (p=0.02). Strikingly, the 5TGM1-shSema4D cells when co-cultured with MC4s did not have the same effect and allowed the upregulation of Runx2 expression on day 5 (p=0.01). Myeloma-conditioned media increased Sema4D expression by OCL throughout the 5 days of differentiation 2 to 3-fold (p=0.01 for day 5). Conclusions: The myeloma cells seem to be utilizing Sema4D both directly and indirectly to inhibit bone formation. Targeted therapy against Sema4D may improve outcomes and fracture-free survival for multiple myeloma patients.
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Ren, Xie, Yao, Yu, Chang, Xing, Zhang, et al. "MiR-125b Suppression Inhibits Apoptosis and Negatively Regulates Sema4D in Avian Leukosis Virus-Transformed Cells." Viruses 11, no. 8 (August 7, 2019): 728. http://dx.doi.org/10.3390/v11080728.
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Subgroup J avian leukosis virus (ALV-J), an oncogenic retrovirus, causes hemangiomas and myeloid tumors in chickens. We previously showed that miR-125b is down-regulated in ALV-J-induced tumors. This study aimed to investigate the possible role of miR-125b in ALV-J-mediated infection and tumorigenesis. Knockdown of miR-125b expression in HP45 cells reduced, whereas over-expression induced late-stage apoptosis. Bioinformatics analysis and luciferase activity assays indicate that miR-125b targets Semaphorin 4D/CD100 (Sema4D) by binding the 3′-untranslated region of messenger RNA (mRNA). Up-regulation of miR-125b in the DF1 cell line suppressed Sema4D expression, whereas miR-125 down-regulation increased Sema4D expression levels. To uncover the function of Sema4D during ALV-J infection, animal infection experiments and in vitro assays were performed and show that Sema4D mRNA levels were up-regulated in ALV-J-infected tissues and cells. Finally, functional experiments show that miR-125 down-regulation and Sema4D over-expression inhibited apoptosis in HP45 cells. These results suggest that miR-125b and its target Sema4D might play an important role in the aggressive growth of HP45 cells induced by avian leukosis viruses (ALVs). These findings improve our understanding of the underlying mechanism of ALV-J infection and tumorigenesis.
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Zhang, Huayu, Dianne Vreeken, Abidemi Junaid, Gangqi Wang, Wendy M. P. J. Sol, Ruben G. de Bruin, Anton Jan van Zonneveld, and Janine M. van Gils. "Endothelial Semaphorin 3F Maintains Endothelial Barrier Function and Inhibits Monocyte Migration." International Journal of Molecular Sciences 21, no. 4 (February 21, 2020): 1471. http://dx.doi.org/10.3390/ijms21041471.
Full textAbstract:
In normal physiology, endothelial cells (ECs) form a vital barrier between the blood and underlying tissue controlling leukocyte diapedesis and vascular inflammation. Emerging data suggest that neuronal guidance cues, typically expressed during development, have roles outside the nervous system in vascular biology and immune responses. In particular, Class III semaphorins have been reported to affect EC migration and angiogenesis. While ECs express high levels of semaphorin 3F (SEMA3F), little is known about its function in mature ECs. Here we show that SEMA3F expression is reduced by inflammatory stimuli and increased by laminar flow. Endothelial cells exposed to laminar flow secrete SEMA3F, which subsequently binds to heparan sulfates on the surface of ECs. However, under pro-inflammatory conditions, reduced levels of SEMA3F make ECs more prone to monocyte diapedesis and display impaired barrier function as measured with an electric cell–substrate impedance sensing system and a microfluidic system. In addition, we demonstrate that SEMA3F can directly inhibit the migration of activated monocytes. Taken together, our data suggest an important homeostatic function for EC-expressed SEMA3F, serving as a mediator of endothelial quiescence.
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Yu, Aijun, Luwen Zhao, Qingmin Kang, Jian Li, Kai Chen, and Hua Fu. "SOX2 knockdown slows cholangiocarcinoma progression through inhibition of transcriptional activation of lncRNA PVT1." Biochemical Journal 477, no. 18 (September 24, 2020): 3527–40. http://dx.doi.org/10.1042/bcj20200219.
Full textAbstract:
Cholangiocarcinoma (CCA) has accounted for a high rate of mortality and morbidity in the recent years. Long non-coding RNAs (lncRNAs) play an important role in different cellular environments, including cancer. As such, they have been used as potential targets during CCA therapy. The objective of this study was to investigate the effects of lncRNA PVT1 on CCA and its mechanisms behind lncRNA PVT1 regulation. The interactions among SOX2, lncRNA PVT1, miR-186 and SEMA4D were verified by chromatin immunoprecipitation, RNA immunoprecipitation and dual luciferase reporter gene assay. Gain- and loss-of-function experiments were conducted to explore the modulatory effects of SOX2, lncRNA PVT1, miR-186 and SEMA4D on cell viability, migration and invasion of CCA by CCK-8 and Transwell assays. In vivo effects of lncRNA PVT1 or SEMA4D were studied in a nude mouse model. MiR-186 was poorly expressed while SOX2, lncRNA PVT1 and SEMA4D were highly expressed in CCA cells. SOX2 induced the transcriptional activation of lncRNA PVT1 expression to promote proliferation, migration and invasion of CCA cells. LncRNA PVT1 bound to miR-186 and miR-186 was found to target SEMA4D. The overexpression of lncRNA PVT1 and SEMA4D, as well as the inhibition of miR-186 led to elevated CCA cell proliferation, migration and invasion. In vivo experiments confirmed the inhibitory role of lncRNA PVT1 knockdown or SEMA4D knockdown in CCA. All in all, SOX2 down-regulated miR-186 through the transcriptional activation of lncRNA PVT1, whereas elevating SEMA4D expression, thus promoting the progression of CCA.
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Zhu, Li, Timothy J. Stalker, Tao Wang, Hong Jiang, Atushi Kumanogoh, Hitoshi Kikutani, Peter Gruber, and Lawrence F. Brass. "Loss of Sema4D Signaling in Platelets Impairs the Formation and Stability of Arterial Thrombi In Vivo and Reduces Myocardial Infarct Size." Blood 110, no. 11 (November 16, 2007): 3631. http://dx.doi.org/10.1182/blood.v110.11.3631.3631.
Full textAbstract:
Abstract Contact-dependent signaling between platelets helps to promote thrombus growth and stability. One mechanism for contact-dependent signaling involves the binding of cell surface ligands to corresponding receptors on the surface of adjacent cells. In our efforts to identify novel participants in this process, we have recently reported that platelets express on their surface the semaphorin family member, sema4D, and its two known receptors, CD72 and plexin-B1 (Zhu, et al, PNAS, 2007). We have also shown that although their initial tail bleeding time is normal, platelets from sema4D(−/−) mice have a defect in collagen-induced signaling and platelet aggregation in vitro. In the present studies, we used matched sema4D(−/−) and wild type (WT) mice to examine the consequences of impaired sema4D signaling in models of platelet function in vivo. In the first model, irradiated Rose Bengal dye was used to produce an arteriolar injury in an exteriorized cremaster muscle. Platelets were identified with a fluorescent CD41 antibody and detected in real time using digital microscopy. The results showed that thrombus formation occurred in all of the mice that were tested, but while stable occlusion was observed in approximately half of the control mice, none of the sema4D(−/−) mice developed stable occlusions during the period of observation (p<0.02). Similarly, when a laser was used to produce a focal injury in cremaster muscle arterioles, both the initial rate of platelet accumulation and the peak extent of accumulation were approximately 50% lower in the sema4D(−/−) mice than in the matched controls. To test the contribution of sema4D to platelet responses in a larger artery, the right common carotid was injured by transient exposure to FeCl3 and changes in flow were measured using a Doppler probe. The results showed that the time to occlusion was 35% greater in the sema4D(−/−) mice than in controls (p<0.02). Furthermore, stable occlusion occurred in only 9 of 16 (56%) sema4D(−/−) mice Vs. 7 of 9 (78%) WT mice. Finally, myocardial infarct size was measured in an ischemia/reperfusion injury model 48 hrs after transient ligation of the left anterior descending coronary artery. Although infarction occurred in all cases, infarct volume was 56% smaller in the sema4D(−/−) mice than the matched controls (p<0.01). In summary, these results show that there is a substantial impairment of platelet function in vivo in mice that lack sema4D. This impairment was observed in both arterioles and arteries using several different methods to evoke platelet activation. When combined with our earlier observations, the results show that signaling by sema4D and its receptors provides a novel mechanism to promote thrombus growth and stability.
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Kang, S. E., S. U. Kim, R. H. Kim, H. J. Yoo, Y. J. Lee, I. A. Choi, J. K. Park, E. Y. Lee, and Y. W. Song. "AB0133 INCREASED SOLUBLE SEMAPHORIN 4D/CD100 IN THE PLASMA OF SJÖGREN’S SYNDROME AND ITS EFFECTS ON HUMAN SALIVARY GLAND CELL AND CD4+ T CELL." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 1367.1–1367. http://dx.doi.org/10.1136/annrheumdis-2020-eular.5162.
Full textAbstract:
Background:Semaphorin 4D (SEMA4D) / CD100, known as a subfamily of axonal guidance proteins, has also been reported to act as an immunoregulator in several infectious and inflammatory diseases [1]. Sjögren’s syndrome (SS) is a systemic autoimmune disease that primarily affects the exocrine glands by infiltrated lymphocytes resulting in dryness of mouth and eyes. IL-17 was reported to impair the integrity of tight junction barrier and attenuate the expression of aquaporin 5 (AQP5), causing salivary gland dysfunction in SS [2].Objectives:This study was aimed to evaluate the role of SEMA4D in patients with SS and investigate the effect of SEMA4D on human salivary gland epithelial cell (SGEC) and T cell.Methods:Soluble SEMA4D levels in plasma were measured by enzyme-linked immunosorbent assay (ELISA) from patients with SS, non-SS sicca and healthy controls. Immortalized human SGECs, originated from acini (NS-SV-AC) and duct (NS-SV-DC), were used to evaluate the effects of SEMA4D. CD4+T cells from human peripheral blood were isolated to determine the secretion of cytokines in response to SEMA4D. IFN-γ and IL-17 were used to determine the effects on AQP5 expression of SGEC.Results:The levels of soluble SEMA4D in plasma were increased in patients with SS (median [interquartile range]: 1221.3 [393.5] pg/mL) compared to non-SS sicca (940.2 [355.1] pg/mL,p= 0.006) or healthy controls (909.5 [108.0] pg/mL,p <0.0001). The levels of soluble SEMA4D in plasma were correlated with the levels of several autoantibodies including anti-SSA (Spearman’s rho = 0.358,p= 0.006), anti-SSB (rho = 0.350,p= 0.007), and anti-muscarinic receptor 3 (M3R) Ab (rho = 0.495,p< 0.001), and also correlated with total IgG (rho = 0.431,p= 0.002). SEMA4D-stimulated SGECs showed decreased expression of tight junctions such as occludin and Zo-1. CD4+T cells secreted IFN-γ (p= 0.025), IL-17 (p= 0.028), and IL-21 (p= 0.007) with SEMA4D stimulation. IFN-γ and IL-17 decreased AQP5 expression in SGECs.Conclusion:SEMA4D contributed to decreased expression of tight junction in SGECs. SEMA4D induced production of IFN-γ and IL-17 in CD4+T cells and these cytokine decreased AQP5 expression in SGECs.References:[1]Worzfeld T, Offermanns S. Nat Rev Drug Discov. 2014;13(8):603-21.[2]Bhattarai KR, Junjappa R, Handigund M, Kim HR, Chae HJ. Autoimmun Rev. 2018;17(4):376-90.Disclosure of Interests:None declared
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Wang, Liu, Xiangfen Li, Yao Song, Dongzhe Song, and Dingming Huang. "The emerging roles of semaphorin4D/CD100 in immunological diseases." Biochemical Society Transactions 48, no. 6 (December 1, 2020): 2875–90. http://dx.doi.org/10.1042/bst20200821.
Full textAbstract:
In vertebrates, the semaphorin family of proteins is composed of 21 members that are divided into five subfamilies, i.e. classes 3 to 7. Semaphorins play crucial roles in regulating multiple biological processes, such as neural remodeling, tissue regeneration, cancer progression, and, especially, in immunological regulation. Semaphorin 4D (SEMA4D), also known as CD100, is an important member of the semaphorin family and was first characterized as a lymphocyte-specific marker. SEMA4D has diverse effects on immunologic processes, including immune cell proliferation, differentiation, activation, and migration, through binding to its specific membrane receptors CD72, PLXNB1, and PLXNB2. Furthermore, SEMA4D and its underlying signaling have been increasingly linked with several immunological diseases. This review focuses on the significant immunoregulatory role of SEMA4D and the associated underlying mechanisms, as well as the potential application of SEMA4D as a diagnostic marker and therapeutic target for the treatment of immunological diseases.
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Zhu, Li, Hong Jiang, Atsushi Kumanogoh, Hitoshi Kikutani, and Lawrence F. Brass. "Defective Activation of Phospholipase Cγ2 by Collagen in Platelets Lacking the Semaphorin Family Member, Sema4D." Blood 110, no. 11 (November 16, 2007): 417. http://dx.doi.org/10.1182/blood.v110.11.417.417.
Full textAbstract:
Abstract Semaphorins are a large family of cell surface molecules best known for their ability to mediate communication between cells during neural development. We have recently shown that human platelets express the semaphorin family member, sema4D, and both of its known receptors, CD72 and plexin-B1 (Zhu, et al, PNAS, 2007). We have also shown that sema4D(−/−) mice have an impaired response to arterial injury in vivo and a selective defect in collagen- and convulxin-induced platelet aggregation in vitro. In the present studies we have sought the molecular basis for these defects, focusing on events downstream of glycoprotein VI (GPVI), which serves as a receptor for both collagen and convulxin. In normal platelets, GPVI signaling leads to the phosphorylation and activation of phospholipase Cγ2 (PLCγ2) through the formation of a signaling complex that includes SLP-76 and LAT. This complex is activated when GPVI-associated FcRγ is phosphorylated, allowing the tyrosine kinase, Syk, to bind. PLCγ2 activation results in phosphoinositide hydrolysis, an IP3-mediated increase in cytosolic Ca++, and activation of additional kinases, such as Akt. In theory, the absence of sema4D could affect any of these steps and by doing so impair collagen-induced platelet aggregation. Working backwards through the GPVI pathway, our results showed that compared to platelets from matched WT mice, sema4D(−/−) platelets have 1) a rightward-shift in the dose/response curve for collagen-induced Akt phosphorylation, 2) a 37% smaller increase in cytosolic Ca++, and 3) a 43% smaller increase in PLCγ2 phosphorylation. However, we found no defect in collagen-induced FcRγ phosphorylation, which is the earliest event in GPVI signaling. The defect in PLCγ2 phosphorylation was not limited to mouse platelets, but was also observed when human platelets were stimulated with collagen in the presence of an antibody directed towards the sema4D extracellular domain. Taken together, these results show that sema4D is needed for optimal activation of PLCγ2 by collagen downstream of the GPVI/FcRγ complex. Sema4D is believed to act in part through contact-dependent binding of sema4D to its receptors, CD72 and plexin-B1. Since these studies were performed under conditions in which platelet:platelet contacts can occur, the observed defect in collagen and convulxin responses could be due to impaired signaling by either of these receptors or, in theory, by retrograde signaling via sema4D. One candidate mechanism involves a regulatory complex between CD72 and the tyrosine phosphatase, SHP-1, which we have shown to occur in resting human platelets and to be lost when platelets are activated by agonists or stimulated by soluble sema4D. In theory, sema4D-dependent loss of the CD72/SHP-1 complex allows SHP-1 to relax into an inactive conformation, promoting protein tyrosine phosphorylation, which would not occur when sema4D is absent or blocked.
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Zhu, Li, Wolfgang Bergmeier, Jie Wu, Hong Jiang, Nana Yeboah, Ran Fan, Marcin Cieslak, Marcos E. Milla, and Lawrence F. Brass. "Regulated Shedding of sema4D from the Platelet Surface Produces a Bioactive Second Messenger in Thrombotic Disorders." Blood 106, no. 11 (November 16, 2005): 1641. http://dx.doi.org/10.1182/blood.v106.11.1641.1641.
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Abstract Proteins that are expressed on the platelet surface can participate in contact-dependent signaling events which modulate thrombus formation or, after being shed from the platelet surface, serve as bioactive messengers that affect the function of nearby cells. Here we show for the first time that platelets express the class IV semaphorin known as sema4D or CD100, and that platelet activation causes the regulated shedding of the sema4D extracellular domain in a biologically-active form. Sema4D is a glycosylated 150 kDa disulfide-linked homodimer that has previously been implicated in interactions between T-cells and B-cells. Platelet activation by collagen, thrombin or PMA causes a transient increase in sema4D surface expression peaking at 15 min, followed by a complete loss of expression over 30–60 minutes. These events are accompanied by the release of the sema4D exodomain as a 130 kDa fragment, leaving a 25–30 kDa transmembrane and cytoplasmic domain fragment that is retained by the platelets. The cleavage event required to produce these fragments is inhibited by metalloprotease inhibitors and abolished in platelets from chimeric mice lacking the metalloprotease known as ADAM17 or TACE (TNF alpha converting enzyme). Incubation of recombinant sema4D with ADAM17 identified a single cleavage site just outside the predicted transmembrane domain. Western blots show that human platelets express ADAM17 in both its immature (zymogen) and mature (active) forms, and indicate that at least some of the ADAM17 is located on the platelet surface. ADAM17-dependent cleavage of sema4D does not require platelet aggregation, but the rate is accelerated when aggregation is allowed to occur and slowed when aggregation is prevented. Under both sets of conditions, cleavage of sema4D occurs to a greater extent and more rapidly than the ADAM17-dependent cleavage of GP Ib alpha, suggesting that there is a hierarchy of proteolytic events when platelets are activated. In terms of biological impact, the shedding of sema4D following platelet activation raises the possibility that the soluble extracellular domain of sema4D serves as a bioactive messenger. Two receptors for sema4D have been identified previously: CD72, which is present on lymphocytes where it regulates the activity of the tyrosine phosphatase, SHP-1, and plexin-B1, which is expressed in endothelial cells. Western blots suggest that both of these receptors are expressed on human platelets and show that SHP-1 is associated with CD72 in resting, but not activated platelets. Taken together, these results demonstrate that sema4D undergoes regulated ADAM17-dependent shedding when platelets are activated, and suggest that this results in the production of a bioactive form of the molecule that can affect responses in nearby platelets, lymphocytes and endothelial cells at sites of thrombosis.
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Wu, Guanlin. "Clinical relevance of semaphorin-3F in patients with prostate cancer." Clinical and Investigative Medicine 42, no. 3 (September 29, 2019): E64—E69. http://dx.doi.org/10.25011/cim.v42i3.33094.
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Purpose: To identify prognosis predictors for patients with prostate cancer (PCa).
Methods: Four independent PCa microarray datasets (GSE32448, GSE16560, GSE79957 and GSE17951) were reanalyzed to characterize the expression of semaphorin-3F (SEMA3F) gene between PCa patients and normal prostate tissues and the correlation between SEMA3F expression and the age, tumor/nodes/metastasis (TNM) staging, Gleason Grade Group, prostate-specific antigen level and overall survival of PCa patients. Gene set enrichment analysis was applied to investigate the potential relevant mechanisms regarding the expression of SEMA3F and the proliferation of PCa cells.
Results: The level of SEMA3F was significantly higher in normal prostate tissues compared with that in PCa cells (P
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Rezaeepoor, Mahsa, Golnaz Rashidi, Mona Pourjafar, Chiman Mohammadi, Ghasem Solgi, and Rezvan Najafi. "SEMA4D Knockdown Attenuates β-Catenin-Dependent Tumor Progression in Colorectal Cancer." BioMed Research International 2021 (July 21, 2021): 1–12. http://dx.doi.org/10.1155/2021/8507373.
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Semaphorin 4D (SEMA4D), a protein originally demonstrated to regulate the immune system and axonal growth cone collapse in the developing central nervous system, is overexpressed in various human malignancies, including colorectal cancer (CRC). This investigation was undertaken to examine the effects of SEMA4D silencing on the biological properties of the CRC cell line. SW48 cells were transfected with a siRNA-targeting SEMA4D. The mRNA expression of underlying pro- and antiapoptotic proteins including Bax, Bcl-2, P53, and caspase-3, cancer stem cell (CSC) markers, epithelial-mesenchymal transition (EMT) markers, MMP-2, and MMP-9 was examined using qRT-PCR. Further, the protein expression of E-cadherin and β-catenin was confirmed by Western blot. SW48 cell migration and MMP activity were detected using scratch and zymography analysis, respectively. Finally, the apoptosis rate was assessed via the flowcytometry test. SEMA4D knock-down was associated with a considerable suppression of in vitro cell viability, EMT-related genes, CSC markers, β-catenin signaling pathway, sphere-forming, cell migration, and MMP-2 activity as well as induction of apoptosis. This study identifies the inhibitory effects of SEMA4D gene silencing on tumor progression. Thereby, this might conclude a possible alternative to cancer therapy by targeting several prominent pathways involved in cancer through SEMA4D suppression.
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Terpos, Evangelos, Efstathios Kastritis, Tina Bagratuni, Dimitrios Christoulas, Athanasios Papatheodorou, Nikolaos Kanellias, Maria Gkotzamanidou, Evangelos Eleutherakis-Papaiakovou, Maria Gavriatopoulou, and Meletios A. Dimopoulos. "Semaphorin-4D and Plexin-B1 Are Elevated in Multiple Myeloma Microenvironment and Possibly Contribute in the Development of Lytic Bone Disease." Blood 120, no. 21 (November 16, 2012): 1819. http://dx.doi.org/10.1182/blood.v120.21.1819.1819.
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Abstract Abstract 1819 Multiple myeloma (MM) is characterized by the presence of osteolytic lesions due to increased bone resorption and reduced osteoblast function. It has been recently reported that, during bone remodeling, osteoclasts express semaphorin 4D (Sema4D), previously shown to be an axon guidance molecule, which potently inhibits bone formation through the suppression of insulin-like growth factor-1 signaling and the modulation of osteoblast motility. Sema4D acts through its binding to its receptor plexin-B1. There is no information in the literature for the role of Sema4D/plexin-B1 signaling in myeloma-related bone disease. To address this issue we evaluated Sema4D and plexin-B1 in the supernatants of six myeloma cell lines (LR5, MR20, L363, U261, H929, and JJN3) and four ovarian cancer cell lines (A2780, C30, OVCA3 and SKOV3) before and after incubation for 24h and 48h with stromal cell line HS5. Furthermore, we measured Sema4D and plexin-B1 in the bone marrow plasma and serum of 72 newly diagnosed patients with MM (37M/35F, median age 70 years) before the administration of any kind of therapy, in 5 newly diagnosed patients with systemic amyloidosis (AL) and in healthy controls (bone marrow plasma, n=5; serum, n=20), gender- and age-matched. Sema4D and plexin-B1 levels were evaluated using ELISA methodology (USCN Life Science Inc., Wuhan, China). In all patients and controls, we also measured serum C-telopeptide of collagen type-I (a bone resorption marker) and bone-specific alkaline phosphatase (a bone formation marker). Evidence of bone involvement in all patients was documented using plain radiographs. Only one myeloma cell line produced high Sema4D (MR20: 104.45 ng/ml) compared to all others (mean±SD: 1.6±1.4 ng/ml), while there were undetectable Sema4D levels in the supernatants of all ovarian cancer cell lines. Regarding plexin-B1, two myeloma cells lines (H929: 25.3 ng/ml and JJN3: 30.8 ng/ml) and two ovarian cancer cell lines (OVCA3: 5125 ng/ml and SKOV3: 3516 ng/ml) produced high levels compared to the other myeloma (4±2.5 ng/ml) and ovarian cancer cell lines (27.6±3.8 ng/ml). The levels of Sema4D and plexin-B1 in the RPMI+FBS were not detectable. The plexin-B1 levels in the supernatants of the myeloma cell lines (76±140 ng/ml) were decreased compared to the respective levels of the ovarian cancer cell lines (963±1440 ng/ml, p=0.008). After incubation for 24h and 48h with stromal cell line HS5 (Sema4D and plexin-B1 level in the HS5 supernatant was not detectable and 464.4 ng/ml, respectively), there was no alteration in the Sema4D levels of the supernatants of both the myeloma and the ovarian cancer cell lines, while there was a 5- to 8- fold increase in the plexin-B1 levels in all studied cell lines. The mean Sema4D levels of the bone marrow plasma of the MM patients were 149 ng/ml (±112 ng/ml) and of the Al patients 232 ng/ml (±113 ng/ml), respectively; both dramatically elevated compared to controls (23±12 ng/ml, p<0.01 and p=0.03, respectively). Similarly, the circulating Sema4D concentrations of MM (71±110 ng/ml) and AL patients (75±94 ng/ml) were increased compared to controls (18±10.9 ng/ml; p<0.001 and p=0.045, respectively). There was a strong correlation of Sema4D levels in the serum and in the bone marrow plasma (r=0.628, p<0.001). Sema4D in MM patients correlated with serum calcium (r=0.628, p<0.001) and ISS stage (p=0.037). There was a trend for higher semaphorin levels in patients with osteolysis in plain radiographs compared to patients with no bone disease (p=0.1). Regarding plexin-B1, its bone marrow plasma and serum levels were increased in myeloma patients compared to controls (44±29 ng/ml vs. 3.4±0.8 ng/ml, p<0.01 and 11±20 ng/ml vs. 2.6±2.7 ng/ml, p=0.01, respectively). Our data suggest that there are increased levels of Sema4D and its receptor plexin-B1 in both the bone marrow plasma and the serum of patients with symptomatic, newly-diagnosed MM. These high sema4D correlated with hypercalcemia and ISS stage and possibly contribute to osteolytic bone disease related to myeloma. Further studies with higher number of patients will reveal the exact role of Sema4D/plexin-B pathway in MM. Disclosures: No relevant conflicts of interest to declare.
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Gurrapu, Sreeharsha, Giulia Franzolin, Damon Fard, Massimo Accardo, Enzo Medico, Ivana Sarotto, Anna Sapino, Claudio Isella, and Luca Tamagnone. "Reverse signaling by semaphorin 4C elicits SMAD1/5- and ID1/3-dependent invasive reprogramming in cancer cells." Science Signaling 12, no. 595 (August 20, 2019): eaav2041. http://dx.doi.org/10.1126/scisignal.aav2041.
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Semaphorins are a family of molecular signals that guide cell migration and are implicated in the regulation of cancer cells. In particular, transmembrane semaphorins are postulated to act as both ligands (“forward” mode) and signaling receptors (“reverse” mode); however, reverse semaphorin signaling in cancer is relatively less understood. Here, we identified a previously unknown function of transmembrane semaphorin 4C (Sema4C), acting in reverse mode, to elicit nonconventional TGF-β/BMP receptor activation and selective SMAD1/5 phosphorylation. Sema4C coimmunoprecipitated with TGFBRII and BMPR1, supporting its role as modifier of this pathway. Sema4C reverse signaling led to the increased abundance of ID1/3 transcriptional factors and to extensive reprogramming of gene expression, which suppressed the typical features of the epithelial-mesenchymal transition in invasive carcinoma cells. This phenotype was nevertheless coupled with burgeoning metastatic behavior in vivo, consistent with evidence that Sema4C expression correlates with metastatic progression in human breast cancers. Thus, Sema4C reverse signaling promoted SMAD1/5- and ID1/3-dependent gene expression reprogramming and phenotypic plasticity in invasive cancer cells.
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Sierra, Jose Rafael, Simona Corso, Luisa Caione, Virna Cepero, Paolo Conrotto, Alessandro Cignetti, Wanda Piacibello, et al. "Tumor angiogenesis and progression are enhanced by Sema4D produced by tumor-associated macrophages." Journal of Experimental Medicine 205, no. 7 (June 16, 2008): 1673–85. http://dx.doi.org/10.1084/jem.20072602.
Full textAbstract:
Increased evidence suggests that cancer-associated inflammation supports tumor growth and progression. We have previously shown that semaphorin 4D (Sema4D), a ligand produced by different cell types, is a proangiogenic molecule that acts by binding to its receptor, plexin B1, expressed on endothelial cells (Conrotto, P., D. Valdembri, S. Corso, G. Serini, L. Tamagnone, P.M. Comoglio, F. Bussolino, and S. Giordano. 2005. Blood. 105:4321–4329). The present work highlights the role of Sema4D produced by the tumor microenvironment on neoplastic angiogenesis. We show that in an environment lacking Sema4D, the ability of cancer cells to generate tumor masses and metastases is severely impaired. This condition can be explained by a defective vascularization inside the tumor. We demonstrate that tumor-associated macrophages (TAMs) are the main cells producing Sema4D within the tumor stroma and that their ability to produce Sema4D is critical for tumor angiogenesis and vessel maturation. This study helps to explain the protumoral role of inflammatory cells of the tumor stroma and leads to the identification of an angiogenic molecule that might be a novel therapeutic target.
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Carvalheiro, Tiago, Carlos Rafael-Vidal, Beatriz Malvar-Fernandez, Ana P. Lopes, Jose M. Pego-Reigosa, Timothy R. D. J. Radstake, and Samuel Garcia. "Semaphorin4A-Plexin D1 Axis Induces Th2 and Th17 While Represses Th1 Skewing in an Autocrine Manner." International Journal of Molecular Sciences 21, no. 18 (September 22, 2020): 6965. http://dx.doi.org/10.3390/ijms21186965.
Full textAbstract:
Semaphorin (Sema)4A is a transmembrane glycoprotein that is elevated in several autoimmune diseases such as systemic sclerosis, rheumatoid arthritis and multiple sclerosis. Sema4A has a key role in the regulation of Thelper Th1 and Th2 differentiation and we recently demonstrated that CD4+ T cell activation induces the expression of Sema4A. However, the autocrine role of Sema4A on Th cell differentiation remains unknown. Naïve Th cells from healthy controls were cell sorted and differentiated into Th1, Th2 and Th17 in the presence or absence of a neutralizing antibody against the Sema4A receptor PlexinD1. Gene expression was determined by quantitative PCR and protein expression by ELISA and flow cytometry. We found that the expression of Sema4A is induced during Th1, Th2 and Th17 differentiation. PlexinD1 neutralization induced the differentiation of Th1 cells, while reduced the Th2 and Th17 skewing. These effects were associated with an upregulation of the transcription factor T-bet by Th1 cells, and to downregulation of GATA3 and RORγt in Th2 cells and Th17 cells, respectively. Finally, PlexinD1 neutralization regulates the systemic sclerosis patients serum-induced cytokine production by CD4+ T cells. Therefore, the autocrine Sema4A-PlexinD1 signaling acts as a negative regulator of Th1 skewing but is a key mediator on Th2 and Th17 differentiation, suggesting that dysregulation of this axis might be implicated in the pathogenesis of CD4+ T cell-mediated diseases.
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Salimi-Sotoodeh, Mehdi, Arash Saffarian, Mousa Taghipour, Amir-Reza Dehghanian, Nooshafarin Chenari, Abbas Ghaderi, and Mahboobeh Razmkhah. "Correlation of Peritumoral Edema and Microvessel Density with Tissue Expression of VEGF, Semaphorins 3A and 3C in Patients with Meningioma." Asian Pacific Journal of Cancer Biology 3, no. 4 (January 6, 2019): 93–98. http://dx.doi.org/10.31557/apjcb.2018.3.4.93-98.
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Background: Several angiogenic factors correlate with angiogenesis in meningioma while their exact role is yet to be identified. Semaphorins are described with a variety of physiological functions including angiogenesis and migration of neural crest cells. Objective: We aimed to determine the correlation of semaphorin 3A, 3C (Sema 3A and 3C) and vascular endothelial growth factor (VEGF) expression with microvessel density (MVD) and peritumoral brain edema (PTBE) in meningioma.Methods: In this study 21 patients with grade I meningioma were included. PTBE was measured on axial and coronal brain MRI. Tissue expression of semaphorin 3A, 3C and VEGF were determined using quantitative real-time PCR (qRT-PCR). Result: We found that mean vascular density and tumor edema index were negatively associated with tissue expression of semaphorin 3A and 3C, respectively (p=0.029 and p=0.048). VEGF did not show statistically significant correlation with tumor characteristics studied (p> 0.05). We also found that the mean vascular density of the menigiomas was positively associated with intra operative blood loss (r=0.503, p=0.010). Conclusion: Our data indicates an inverse correlation of Sema3A and Sema3C with vascular density and peritumoral edema, respectively, while no correlation could be shown for VEGF. Thus, Sema3A and 3C may be identified as appropriate inhibitors of pathological angiogenesis in human meningioma. However, confirmation of this finding in a larger dataset is warranted.
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Huang, Junhua, Shouzhen Wu, Sancheng Cao, Xieying Zhu, and Shuwan Zhang. "Neutrophil-Derived Semaphorin 4D Induces Inflammatory Cytokine Production of Endothelial Cells via Different Plexin Receptors in Kawasaki Disease." BioMed Research International 2020 (December 16, 2020): 1–11. http://dx.doi.org/10.1155/2020/6663291.
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Inflammation of endothelial cells (ECs) plays an important role in the pathogenesis of coronary artery lesions (CALs) in Kawasaki disease (KD). Semaphorin 4D (Sema4D) is the first semaphorin shown to have immunoregulatory functions by interacting with its receptors—plexin Bs. Recently, Sema4D has been reported to exert a proinflammatory effect on the endothelium and to be involved in cardiovascular disease. However, the role of Sema4D in KD remains unknown. This study was aimed at revealing the change of soluble Sema4D (sSema4D) in the serum of patients with KD and the effect of the sSema4D-plexin axis on the production of proinflammatory cytokines from human coronary endothelial cells (HCAECs) stimulated with sera from KD patients. Our results showed that serum sSema4D levels were specifically elevated in KD patients, especially in those with CALs, and correlated positively with disease severity and serum concentrations of interleukin- (IL-) 1β, IL-6, and IL-8. The disintegrin and metalloproteinase domain 17- (AMAM17-) mediated Sema4D shedding from neutrophils contributed to the elevation of sSema4D in the serum of KD patients. Furthermore, we found that Sema4D induced IL-1β production of HCAECs via plexin B2, whereas it promoted IL-6 and IL-8 production via plexin B1. Moreover, the expression of both plexin B1 and plexin B2 was upregulated in HCAECs treated with KD sera, and silencing of the two plexin receptors suppressed the overexpression of IL-1β, IL-6, and IL-8 in KD serum-treated HCAECs. Thus, our findings indicated that sSema4D released from neutrophils participates in the pathogenesis of KD-CALs by promoting inflammatory cytokine production of ECs via both plexin B1 and plexin B2, and Sema4D may be a novel predictor for KD-CALs and a candidate therapeutic target for anti-inflammatory strategies of KD.