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1
Larson, Sandy R., Stacey Thomas, Shaikh M. Atif, Sophie Gibbings, Miglena Prabagar, Peter M. Henson, and Claudia Jakubzick. "Ly6C+ monocyte efferocytosis and cross-presentation of cell-associated antigen." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 116.12. http://dx.doi.org/10.4049/jimmunol.196.supp.116.12.
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Abstract Recently it was shown that circulating Ly6C+ monocytes traffic from tissue to the draining lymph nodes (LNs) with minimal alteration in their overall phenotype. Furthermore, in the steady state, Ly6C+ monocytes are as abundant as classical dendritic cells (DCs) within the draining LNs, and even more abundant during inflammation. However, little is known about the functional roles of constitutively trafficking Ly6C+ monocytes. In this study we investigated whether Ly6C+ monocytes can efferocytose (acquire dying cells) and cross-present cell-associated antigen, a functional property specially attributed to Batf3+ DCs. We demonstrated that Ly6C+ monocytes intrinsically efferocytose and cross-present cell-associated antigen to CD8+ T cells. In addition, efferocytosis was enhanced upon direct activation of the Ly6C+ monocytes through its corresponding TLRs, TLR4 and TLR7. However, only ligation of TLR7, and not TLR4, enhanced cross-presentation by Ly6C+ monocytes. Overall, this study outlines two functional roles, among others, that Ly6C+ monocytes have during an adaptive immune response.
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Vetter, Mathieu, and Philippe Saas. "« Fort comme la mort », où comment l’efferocytose contrôle la résolution de l’inflammation." médecine/sciences 40, no. 5 (May 2024): 428–36. http://dx.doi.org/10.1051/medsci/2024050.
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L’arrêt de la réponse inflammatoire, ou résolution de l’inflammation, est considéré aujourd’hui comme un processus actif lié à la production (ou à la libération) de composés anti-inflammatoires aussi appelés composés pro-résolutifs. L’évènement permettant d’enclencher la résolution de l’inflammation est l’élimination des cellules immunitaires apoptotiques par les macrophages, un processus nommé efferocytose, dont l’altération est à l’origine de différentes maladies. Dans cette synthèse, nous décrivons les étapes de cette efferocytose et les mécanismes qui en résultent et permettent de stopper l’inflammation. Nous évoquerons également de nouvelles pistes thérapeutiques fondées sur les facteurs pro-résolutifs : la thérapie résolutive.
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Higham, Andrew, Tom Scott, Jian Li, Rosemary Gaskell, Aisha Baba Dikwa, Rajesh Shah, M. Angeles Montero-Fernandez, Simon Lea, and Dave Singh. "Effects of corticosteroids on COPD lung macrophage phenotype and function." Clinical Science 134, no. 7 (April 2020): 751–63. http://dx.doi.org/10.1042/cs20191202.
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Abstract The numbers of macrophages are increased in the lungs of chronic obstructive pulmonary disease (COPD) patients. COPD lung macrophages have reduced ability to phagocytose microbes and efferocytose apoptotic cells. Inhaled corticosteroids (ICSs) are widely used anti-inflammatory drugs in COPD; however, their role beyond suppression of cytokine release has not been explored in COPD macrophages. We have examined the effects of corticosteroids on COPD lung macrophage phenotype and function. Lung macrophages from controls and COPD patients were treated with corticosteroids; effects on gene and protein expression of CD163, CD164, CD206, MERTK, CD64, CD80 and CD86 were studied. We also examined the effect of corticosteroids on the function of CD163, MERTK and cluster of differentiation 64 (CD64). Corticosteroid increased CD163, CD164, CD206 and MERTK expression and reduced CD64, CD80 and CD86 expression. We also observed an increase in the uptake of the haemoglobin–haptoglobin complex (CD163) from 59 up to 81% and an increase in efferocytosis of apoptotic neutrophils (MERTK) from 15 up to 28% following corticosteroid treatment. We observed no effect on bacterial phagocytosis. Corticosteroids alter the phenotype and function of COPD lung macrophages. Our findings suggest mechanisms by which corticosteroids exert therapeutic benefit in COPD, reducing iron available for bacterial growth and enhancing efferocytosis.
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Lam, Austin Le, and Bryan Heit. "Having an Old Friend for Dinner: The Interplay between Apoptotic Cells and Efferocytes." Cells 10, no. 5 (May 20, 2021): 1265. http://dx.doi.org/10.3390/cells10051265.
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Apoptosis, the programmed and intentional death of senescent, damaged, or otherwise superfluous cells, is the natural end-point for most cells within multicellular organisms. Apoptotic cells are not inherently damaging, but if left unattended, they can lyse through secondary necrosis. The resulting release of intracellular contents drives inflammation in the surrounding tissue and can lead to autoimmunity. These negative consequences of secondary necrosis are avoided by efferocytosis—the phagocytic clearance of apoptotic cells. Efferocytosis is a product of both apoptotic cells and efferocyte mechanisms, which cooperate to ensure the rapid and complete removal of apoptotic cells. Herein, we review the processes used by apoptotic cells to ensure their timely removal, and the receptors, signaling, and cellular processes used by efferocytes for efferocytosis, with a focus on the receptors and signaling driving this process.
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Aitcheson, Savannah M., Francesca D. Frentiu, Sheree E. Hurn, Katie Edwards, and Rachael Z. Murray. "Skin Wound Healing: Normal Macrophage Function and Macrophage Dysfunction in Diabetic Wounds." Molecules 26, no. 16 (August 13, 2021): 4917. http://dx.doi.org/10.3390/molecules26164917.
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Macrophages play a prominent role in wound healing. In the early stages, they promote inflammation and remove pathogens, wound debris, and cells that have apoptosed. Later in the repair process, they dampen inflammation and secrete factors that regulate the proliferation, differentiation, and migration of keratinocytes, fibroblasts, and endothelial cells, leading to neovascularisation and wound closure. The macrophages that coordinate this repair process are complex: they originate from different sources and have distinct phenotypes with diverse functions that act at various times in the repair process. Macrophages in individuals with diabetes are altered, displaying hyperresponsiveness to inflammatory stimulants and increased secretion of pro-inflammatory cytokines. They also have a reduced ability to phagocytose pathogens and efferocytose cells that have undergone apoptosis. This leads to a reduced capacity to remove pathogens and, as efferocytosis is a trigger for their phenotypic switch, it reduces the number of M2 reparative macrophages in the wound. This can lead to diabetic foot ulcers (DFUs) forming and contributes to their increased risk of not healing and becoming infected, and potentially, amputation. Understanding macrophage dysregulation in DFUs and how these cells might be altered, along with the associated inflammation, will ultimately allow for better therapies that might complement current treatment and increase DFU’s healing rates.
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Myers, Kayla V., Amber E. de Groot, Anna L. Gonye, Luke V. Loftus, Sarah R. Amend, and Kenneth J. Pienta. "Abstract 2546: Targeting MerTK-mediated efferocytosis in the prostate cancer TME." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2546. http://dx.doi.org/10.1158/1538-7445.am2022-2546.
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Abstract The prostate cancer tumor microenvironment (TME) is comprised of many different components and cell types that influence tumor progression and patient outcome. Macrophages are highly abundant immune cells in the prostate cancer TME. Macrophage phenotypes can be modeled on a continuous spectrum of M1-like (anti-tumor macrophages) to M2-like (pro-tumor macrophages) and most macrophages in the prostate cancer TME are M2-like. Efferocytosis, the phagocytosis of apoptotic cells, is a pro-tumor function of M2-like macrophages. We have developed a flow cytometry assay to quantify efferocytosis of the prostate cancer cell line LNCaP. With both cell line-based THP-1 macrophages and human monocyte-derived macrophages (HMDMs), we observe that M2 macrophages efferocytose LNCaP cells more than M1 macrophages. Based on literature from other models and contexts, efferocytosis further supports the M2-like phenotype. Efferocytosis also prevents the apoptotic cell from progressing to secondary necrosis, which would attract an M1-like macrophage phenotype. Due these aspects, we hypothesize efferocytosis in the prostate cancer TME is a tumor-promoting function of macrophages. Following efferocytosis of LNCaP cells by M2 HMDMs, we detect a decrease in the M1-like, anti-tumor marker CD80 and an increase in M2-like, pro-tumor markers CD206 and PDL1. Due to this role in modulating macrophage phenotype, we hypothesize targeting efferocytosis will slow prostate cancer growth and promote an anti-tumor immune infiltrate, including M1-like macrophages. MerTK is a receptor tyrosine kinase that mediates efferocytosis by binding phosphatidylserine on apoptotic cells. At both the protein and mRNA level, we detect higher MerTK expression in M2 than M1 THP-1 macrophages and HMDMs. Upon addition of apoptotic LNCaP cells, we observe an increase in phosphorylated MerTK (active form), suggesting the role of MerTK in prostate cancer cell efferocytosis. Currently, we are targeting MerTK to block prostate cancer cell efferocytosis in vitro and in vivo. We have generated a Mertk-/-, Hi-Myc mouse model on the FVB/N background. This prostate cancer GEMM will be used to assess the role of MerTK across different stages of prostate cancer progression. We will be comparing tumor size and immune infiltration between Mertk+/+ and Mertk-/- Hi-Myc mice aged to 2 months, 6 months and 12 months. We predict that the Mertk-/- mice will have smaller tumors and an overall anti-tumor immune infiltrate compared to Mertk+/+ mice in this model due to lack of efferocytosis. Citation Format: Kayla V. Myers, Amber E. de Groot, Anna L. Gonye, Luke V. Loftus, Sarah R. Amend, Kenneth J. Pienta. Targeting MerTK-mediated efferocytosis in the prostate cancer TME [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2546.
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Banerjee, Somenath, Jagdish C. Joshi, Vijayalakshmi Yalagala, and Dolly Mehta. "Loss of myeloid S1PR1 makes dysfunctional alveolar macrophages and vascular injury by inducing myeloid bias." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 112.17. http://dx.doi.org/10.4049/jimmunol.206.supp.112.17.
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Abstract Alveolar macrophages (AM) are the most abundant resident innate immune cells in the lungs and directly communicate with both the non-sterile external environment and the pulmonary epithelium. AM initially trigger protective inflammation upon sensing pathogen but later induce lung repair by clearing dead cells, known as efferocytosis, and dampening of inflammation. Studies show that monocytes recruited in the airspace during injury gain AM signature and contribute in lung repair. Sphingosine 1 phosphate receptor 1 (S1PR1), is widely studied in lung endothelium as a barrier protective mechanism and in immune cells in context of trafficking and inflammation but has not yet extensively studied in respect to origin and function of AM. Here, we deleted S1PR1 in mice by crossing S1PR1f/f with LysMCre (S1PR1ΔLyz) mice to investigate the role of S1PR1 in myeloid cells in the mechanism of lung injury. We show that loss of S1PR1 in myeloid cells of mice (S1PR1ΔLyz mice) has 3-fold higher AM pool but surprisingly these mice showed defective lung fluid balance basally or post LPS challenge (intratracheal 0.5 mg/kg). We found that S1PR1−/−AM produced markedly less pro-inflammatory cytokines (IL1b and TNFa) and could not efferocytose. Intriguingly, S1PR1 deficiency induced myeloid biased haematopoiesis as evident from less erythroid progenitor (~0.75 fold) and B cells (~0.82 fold) in bone marrow of S1PR1ΔLyz mice leading to increased circulating monocytes. panRNAseq of S1PR1−/− AM showed markedly reduced Sphk1 and NFκB1 expression and increased expression of KLF4, Myb, Myc, TLR7 & 8. These findings indicate that loss of S1PR1 misfires the generation of incompetent monocytes leading to dysfunctional AM and defective lung repair.
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Abbasi, Muddasir H., Nimra Shehzadi, Arooj Safdar, Rabia Aslam, Arsha Tariq, Misbah Shahid, Azka Zafar, Nadeem Sheikh, and Muhammad Babar Khawar. "Role of Efferocytosis in Health and Diseases." Albus Scientia 2024, no. 1 (May 18, 2024): 1–12. http://dx.doi.org/10.56512/as.2024.1.e240518.
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Efferocytosis is the process of removal of apoptotic cells through phagocytosis by the specialized cells known as efferocytes. Clearance of dead cells also plays an important role in the defensive system of organisms as efferocytosis maintains homeostasis and repairing of tissues and organs. In this process, the dying cell releases signals for identification and engulfment which is further processed by macrophages. Efferocytosis prevents the secondary necrosis and release of pro-inflammatory cellular contents. This clearance process involves interplay of signaling molecules, receptors, and other mediators that ensures prompt recognitions and removal of dying cells. Dysregulation of efferocytosis has been implicated in various pathological conditions, including autoimmune diseases, chronic inflammation, and atherosclerosis. This review focuses on some common autoimmune diseases, cardiovascular diseases, respiratory disorders, and neurodegenerative disorders due to impaired efferocytosis. To describe the pathophysiology of efferocytosis in diseases more extensive studies are required.
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Li, Vivien, Michele D. Binder, and Trevor J. Kilpatrick. "The Tolerogenic Influence of Dexamethasone on Dendritic Cells Is Accompanied by the Induction of Efferocytosis, Promoted by MERTK." International Journal of Molecular Sciences 24, no. 21 (November 2, 2023): 15903. http://dx.doi.org/10.3390/ijms242115903.
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Many treatments for autoimmune diseases, caused by the loss of immune self-tolerance, are broadly immunosuppressive. Dendritic cells (DCs) can be induced to develop anti-inflammatory/tolerogenic properties to suppress aberrant self-directed immunity by promoting immune tolerance in an antigen-specific manner. Dexamethasone can generate tolerogenic DCs and upregulates MERTK expression. As MERTK can inhibit inflammation, we investigated whether dexamethasone’s tolerogenic effects are mediated via MERTK, potentially providing a novel therapeutic approach. Monocyte-derived DCs were treated with dexamethasone, and with and without MERTK ligands or MERTK inhibitors. Flow cytometry was used to assess effects of MERTK modulation on co-stimulatory molecule expression, efferocytosis, cytokine secretion and T cell proliferation. The influence on expression of Rab17, which coordinates the diversion of efferocytosed material away from cell surface presentation, was assessed. Dexamethasone-treated DCs had upregulated MERTK expression, decreased expression of co-stimulatory molecules, maturation and proliferation of co-cultured T cells and increased uptake of myelin debris. MERTK ligands did not potentiate these properties, whilst specific MERTK inhibition only reversed dexamethasone’s effect on myelin uptake. Cells undergoing efferocytosis had higher Rab17 expression. Dexamethasone-enhanced efferocytosis in DCs is MERTK-dependent and could exert its tolerogenic effects by increasing Rab17 expression to prevent the presentation of efferocytosed material on the cell surface to activate adaptive immune responses.
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Poe, S. L., M. Arora, T. B. Oriss, M. Yarlagadda, K. Isse, A. Khare, D. E. Levy, et al. "STAT1-regulated lung MDSC-like cells produce IL-10 and efferocytose apoptotic neutrophils with relevance in resolution of bacterial pneumonia." Mucosal Immunology 6, no. 1 (July 11, 2012): 189–99. http://dx.doi.org/10.1038/mi.2012.62.
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Jondle, Christopher Ned, Bibhuti Mishra, and Jyotika Sharma. "Impact of Klebsiella pneumoniae on efferocytosis of polymorphonuclear cells." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 131.4. http://dx.doi.org/10.4049/jimmunol.196.supp.131.4.
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Abstract Efficient clearance of invading pathogen and the infiltrating cells by phagocytic cells are two key events that are required for successful elimination of a pathological insult. Clearance of the pathogen is usually achieved by phagocytosis and dead cells are cleared by a process called efferocytosis. While there is substantial information on various strategies employed by a number of pathogens to subvert phagocytosis, our knowledge about inhibition of efferocytosis by microbes is extremely limited. In that regard, we observed that, polymorphonuclear cells (PMNs) infected with Klebsiella pneumoniae (KPn), an opportunistic pathogen and a frequent cause of nosocomial infections leading to sepsis, were efferocytosed less than their uninfected counterparts. This inhibition did not correlate with the infection induced effect on phosphatidylserine (PS) exposure, a well-studied “eat me” signal recognized by efferocytic cells or p53 expression, as a marker of apoptosis in PMNs. We further observed that bacterial replication is required for the full inhibitory effect on efferocytosis since heat-killed KPn were not as effective in inhibiting efferocytosis of PMNs. Next we examined the possible role of LPS in diminishing effecrocytosis, given that KPn is a Gram-negative bacterium. By utilizing cells deficient in TLR-4 (a receptor for LPS) and direct stimulation with LPS we determined that LPS is able to directly inhibit efferocytosis of PMNs. To our knowledge, this study is the first to show a modulatory effect of KPn infection and LPS on PMNs leading to inhibition of their efferocytic uptake by macrophages. This could have implications in acute and chronic airway inflammatory diseases such as pneumonia, sepsis, cystic fibrosis, and COPD.
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Thomas, Sean M., Kathryn Wierenga, James Pestka, and Andrew J. Olive. "Functional characterization of a self-replicating and genetically tractable murine alveolar macrophage model." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 17.28. http://dx.doi.org/10.4049/jimmunol.206.supp.17.28.
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Abstract Alveolar macrophages (AMs) are a critical element of the innate immune response to inhaled agents, yet functional and genetic studies of this unique macrophage population are lacking. Current strategies to obtain large quantities of AMs are cumbersome and inefficient. This is due largely to both the high cost of time and resources involved in the extraction of AMs and the inability to effectively culture AMs ex vivo for extended periods of time. While bone marrow derived macrophages (BMDMs) are modeled in numerous immortalized cell lines, AMs currently lack an acceptable model that can be used in vitro. Recently, self-replicating cells derived from the fetal mouse liver, termed “MPI” cells, have been shown to possess AM-like characteristics. Here, we show that early after isolation, these cells are SiglecFhi, Cd11chi, and Cd14low, while also expressing high levels of Pparg, Marco, Itgax, and Car4, akin to AMs. Additionally, like AMs, MPI cells effectively efferocytose dead cell debris and phagocytose silica particles. While these cells lose their “AM-likeness” over time, addition of the cytokine TGF-β dramatically delays this shift away from the AM-like phenotype. Gene expression analysis shows that in contrast to cells treated with TGF-β, untreated MPI cells cease expressing Tgfbr1, the receptor for TGF-β, concurrent with the shift away from the AM-phenotype. Further, these cells are amenable to viral transduction, and we have successfully employed CRISPR/Cas9 targeted genetic editing in MPI cells. These findings further our understanding of MPI cells as an accessible and genetically tractable model for AMs that allow for long-term and large-scale studies that are not possible with AMs isolated ex vivo.
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Kumar, Sushil, and Raymond B. Birge. "Efferocytosis." Current Biology 26, no. 13 (July 2016): R558—R559. http://dx.doi.org/10.1016/j.cub.2016.01.059.
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Guan, Xiaoyue, Yuting Wang, Wenlan Li, Wenli Mu, Yifei Tang, Mingfei Wang, Abdelrahman Seyam, Yao Yang, Lifei Pan, and Tiezhou Hou. "The Role of Macrophage Efferocytosis in the Pathogenesis of Apical Periodontitis." International Journal of Molecular Sciences 25, no. 7 (March 29, 2024): 3854. http://dx.doi.org/10.3390/ijms25073854.
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Macrophages (Mφs) play a crucial role in the homeostasis of the periapical immune micro-environment caused by bacterial infection. Mφ efferocytosis has been demonstrated to promote the resolution of multiple infected diseases via accelerating Mφ polarization into M2 type. However, the Mφ efferocytosis–apical periodontitis (AP) relationship has not been elucidated yet. This study aimed to explore the role of Mφ efferocytosis in the pathogenesis of AP. Clinical specimens were collected to determine the involvement of Mφ efferocytosis in the periapical region via immunohistochemical and immunofluorescence staining. For a further understanding of the moderator effect of Mφ efferocytosis in the pathogenesis of AP, both an in vitro AP model and in vivo AP model were treated with ARA290, a Mφ efferocytosis agonist. Histological staining, micro-ct, flow cytometry, RT-PCR and Western blot analysis were performed to detect the inflammatory status, alveolar bone loss and related markers in AP models. The data showed that Mφ efferocytosis is observed in the periapical tissues and enhancing the Mφ efferocytosis ability could effectively promote AP resolution via facilitating M2 Mφ polarization. Collectively, our study demonstrates the functional importance of Mφ efferocytosis in AP pathology and highlights that accelerating Mφ efferocytosis via ARA290 could serve as an adjuvant therapeutic strategy for AP.
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Tabas, Ira, and Karin E. Bornfeldt. "Intracellular and Intercellular Aspects of Macrophage Immunometabolism in Atherosclerosis." Circulation Research 126, no. 9 (April 24, 2020): 1209–27. http://dx.doi.org/10.1161/circresaha.119.315939.
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Macrophage immunometabolism, the changes in intracellular metabolic pathways that alter the function of these highly plastic cells, has been the subject of intense interest in the past few years, in part because macrophage immunometabolism plays important roles in atherosclerosis and other inflammatory diseases. In this review article, part of the Compendium on Atherosclerosis , we introduce the concepts of (1) intracellular immunometabolism—the canonical pathways of intrinsic cell activation leading to changes in intracellular metabolism, which in turn alter cellular function; and (2) intercellular immunometabolism—conditions in which intermediates of cellular metabolism are transferred from one cell to another, thereby altering the function of the recipient cell. The recent discovery that the metabolite cargo of dead and dying cells ingested through efferocytosis by macrophages can alter metabolic pathways and downstream function of the efferocyte is markedly changing the way we think about macrophage immunometabolism. Metabolic transitions of macrophages contribute to their functions in all stages of atherosclerosis, from lesion initiation to formation of advanced lesions characterized by necrotic cores, to lesion regression following aggressive lipid lowering. This review article discusses recent advances in our understanding of these different aspects of macrophage immunometabolism in atherosclerosis. With the increasing understanding of the roles of macrophage immunometabolism in atherosclerosis, new exciting concepts and potential targets for intervention are emerging.
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Vandivier, R. William, Tiffany R. Richens, Sarah A. Horstmann, Aimee M. deCathelineau, Moumita Ghosh, Susan D. Reynolds, Yi-Qun Xiao, et al. "Dysfunctional cystic fibrosis transmembrane conductance regulator inhibits phagocytosis of apoptotic cells with proinflammatory consequences." American Journal of Physiology-Lung Cellular and Molecular Physiology 297, no. 4 (October 2009): L677—L686. http://dx.doi.org/10.1152/ajplung.00030.2009.
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Cystic fibrosis (CF) is caused by mutated CF transmembrane conductance regulator (CFTR) and is characterized by robust airway inflammation and accumulation of apoptotic cells. Phagocytosis of apoptotic cells (efferocytosis) is a pivotal regulator of inflammation, because it prevents postapoptotic necrosis and actively suppresses release of a variety of proinflammatory mediators, including IL-8. Because CF is associated with accumulation of apoptotic cells, inappropriate levels of IL-8, and robust inflammation, we sought to determine whether CFTR deficiency specifically impairs efferocytosis and its regulation of inflammatory mediator release. Here we show that CFTR deficiency directly interferes with efferocytosis by airway epithelium, an effect that is not due to altered binding of apoptotic cells to epithelial cells or altered expression of efferocytosis receptors. In contrast, expression of RhoA, a known negative regulator of efferocytosis, is substantially increased in CFTR-deficient cells, and inhibitors of RhoA or its downstream effector Rho kinase normalize efferocytosis in these cells. Impaired efferocytosis appears to be mediated through an amiloride-sensitive ion channel, because amiloride restores phagocytic competency in CFTR-deficient cells. Finally, ineffective efferocytosis in CFTR-deficient cells appears to have proinflammatory consequences, because apoptotic cells enhance IL-8 release by these cells, but not by wild-type controls. Therefore, in CF, dysregulated efferocytosis may lead to accumulation of apoptotic cells and impaired regulation of the inflammatory response and, ultimately, may suggest a new therapeutic target.
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Schilke, Robert Michael, Cassidy M. R. Blackburn, Shashanka Rao, David M. Krzywanski, and Matthew D. Woolard. "Macrophage-associated lipin-1 regulates lipid catabolism to promote effective efferocytosis." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 69.22. http://dx.doi.org/10.4049/jimmunol.204.supp.69.22.
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Abstract Failure to resolve inflammation leads to numerous chronic diseases. Disease resolution requires the effective removal of dead cells by macrophage-mediated efferocytosis. Excess lipid accumulation within macrophages can lead to dysfunction that promotes disease pathogenesis. Efferocytosis results in a significant accumulation of lipid inside the macrophage, yet macrophage continue to function. This suggest that during efferocytosis, macrophages have pathways to ameliorate the high lipid load. We have identified that lipin-1, a regulator of lipid metabolism, is critical to proper macrophage responses during efferocytosis. Lipin-1 is a phosphatidic acid phosphatase that also functions as a transcriptional coregulator. We used mice that lack either lipin-1 enzymatic activity or both functions in myeloid cells to define how lipin-1 regulates excess lipids during efferocytosis. We have demonstrated that mice lacking myeloid-associated lipin-1 have diminished apoptotic cell (AC) clearance in a zymozan model of efferocytosis. Clearance of lipids during efferocytosis is accomplished through beta-oxidation. Bone marrow derived macrophages lacking lipin-1 have reduced oxidative respiration in response to both AC and purified palmitate (lipid), indicating defective lipid catabolism. These data suggest that lipin-1 regulates mitochondrial lipid catabolism to reduce lipid burden during efferocytosis. These studies highlight regulation of lipid metabolic pathways in macrophages during efferocytosis that allow them to handle excess lipid burden and promote disease resolution.
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Yanagihashi, Yuichi, Katsumori Segawa, Ryota Maeda, Yo-ichi Nabeshima, and Shigekazu Nagata. "Mouse macrophages show different requirements for phosphatidylserine receptor Tim4 in efferocytosis." Proceedings of the National Academy of Sciences 114, no. 33 (August 2, 2017): 8800–8805. http://dx.doi.org/10.1073/pnas.1705365114.
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Protein S (ProS) and growth arrest-specific 6 (Gas6) bind to phosphatidylserine (PtdSer) and induce efferocytosis upon binding TAM-family receptors (Tyro3, Axl, and Mer). Here, we produced mouse ProS, Gas6, and TAM-receptor extracellular region fused to IgG fragment crystallizable region in HEK293T cells. ProS and Gas6 bound Ca2+ dependently to PtdSer (Kd 20–40 nM), Mer, and Tyro3 (Kd 15–50 nM). Gas6 bound Axl strongly (Kd < 1.0 nM), but ProS did not bind Axl. Using NIH 3T3-based cell lines expressing a single TAM receptor, we showed that TAM-mediated efferocytosis was determined by the receptor-binding ability of ProS and Gas6. Tim4 is a membrane protein that strongly binds PtdSer. Tim4 alone did not support efferocytosis, but enhanced TAM-dependent efferocytosis. Resident peritoneal macrophages, Kupffer cells, and CD169+ skin macrophages required Tim4 for TAM-stimulated efferocytosis, whereas efferocytosis by thioglycollate-elicited peritoneal macrophages or primary cultured microglia was TAM dependent, but not Tim4 dependent. These results indicate that TAM and Tim4 collaborate for efficient efferocytosis in certain macrophage populations.
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Zheng, Wenxue, Zhengjie Zhou, Xiaoping Guo, Xu Zuo, Jiaqi Zhang, Yiming An, Haoyu Zheng, Yuan Yue, Guoqiang Wang, and Fang Wang. "Efferocytosis and Respiratory Disease." International Journal of Molecular Sciences 24, no. 19 (October 3, 2023): 14871. http://dx.doi.org/10.3390/ijms241914871.
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Cells are the smallest units that make up living organisms, which constantly undergo the processes of proliferation, differentiation, senescence and death. Dead cells need to be removed in time to maintain the homeostasis of the organism and keep it healthy. This process is called efferocytosis. If the process fails, this may cause different types of diseases. More and more evidence suggests that a faulty efferocytosis process is closely related to the pathological processes of respiratory diseases. In this review, we will first introduce the process and the related mechanisms of efferocytosis of the macrophage. Secondly, we will propose some methods that can regulate the function of efferocytosis at different stages of the process. Next, we will discuss the role of efferocytosis in different lung diseases and the related treatment approaches. Finally, we will summarize the drugs that have been applied in clinical practice that can act upon efferocytosis, in order to provide new ideas for the treatment of lung diseases.
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Juban, Gaëtan, and Bénédicte Chazaud. "Efferocytosis during Skeletal Muscle Regeneration." Cells 10, no. 12 (November 23, 2021): 3267. http://dx.doi.org/10.3390/cells10123267.
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Efferocytosis, i.e., engulfment of dead cells by macrophages, is a crucial step during tissue repair after an injury. Efferocytosis delineates the transition from the pro-inflammatory phase of the inflammatory response to the recovery phase that ensures tissue reconstruction. We present here the role of efferocytosis during skeletal muscle regeneration, which is a paradigm of sterile tissue injury followed by a complete regeneration. We present the molecular mechanisms that have been described to control this process, and particularly the metabolic control of efferocytosis during skeletal muscle regeneration.
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Tsay, Gregory, Ting-Yin Xue, Fei-Hung Hsieh, Jun-Chieh Tsay, Hsin-Yi Peng, Yung-Ju Yeh, Yen-Chi Tsao, et al. "Hydroxychloroquine and its derivative enhance efferocytosis and modulate the gut microbiome in pristane-induced lupus mice." Journal of Immunology 212, no. 1_Supplement (May 1, 2024): 0435_4594. http://dx.doi.org/10.4049/jimmunol.212.supp.0435.4594.
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Abstract Background Impaired clearance of apoptotic cells (efferocytosis) and microbiota dysbiosis is related to pathogenesis of systemic lupus erythematosus (SLE). Hydroxychloroquine (HCQ) is frequently prescribed for the treatment of SLE. Here, we evaluate changes in efferocytosis and the gut microbiome in mice with pristane-induced lupus (PIL) by HCQ administration. Methods PIL mice were studied with or without HCQ, the HCQ derivatives were modified from HCQ by molecular modification. Efferocytosis was determined in RAW 264.7 cells and peritoneal macrophages from mouse ascites fluid. The gut microbiome was analyzed using Illumina sequencing. Results HCQ enhanced efferocytosis in RAW 264.7 cells, the HCQ derivative AL127 also much enhanced efferocytosis. HCQ also significantly suppressed ascites production of proinflammatory cytokines interleukin (IL)-6 and tumor necrosis factor alpha (TNF-α) in PIL mice. The Firmicutes/Bacteroidetes (F/B) ratio was notably decreased in comparison to untreated controls (p<0.05). Furthermore, administration of HCQ in PIL mice resulted in an increased F/B ratio. Conclusions In this study, both HCQ and its derivative exhibited a capacity to enhance efferocytosis in RAW 264.7 cells and peritoneal macrophages of PIL mice. Furthermore, HCQ treatment reversed the pristane-induced reduction in the Firmicutes/Bacteroidetes (F/B) ratio. These findings underscore the roles of HCQ in facilitating efferocytosis.
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Purnama, Chandra Agung, Anna Meiliana, Melisa Intan Barliana, Keri Lestari, and Andi Wijaya. "The Important Role of Phosphatidylserine, ADAM17, TNF-Alpha, and Soluble MER on Efferocytosis Activity in Central Obesity." Journal of Obesity 2024 (March 20, 2024): 1–10. http://dx.doi.org/10.1155/2024/1424404.
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Background. Obesity is expected to hinder efferocytosis due to ADAM17-mediated cleavage of the MER tyrosine kinase receptor, producing soluble MER (sMER) that disrupts MERTK binding to cell death markers. However, the intracellular efferocytosis pathway in central obesity remains elusive, particularly the role of low-grade chronic inflammation in its initiation and identification of binding signals that disrupt efferocytosis. Objective. We investigate the efferocytosis signaling pathway in men with central obesity and its relationship with inflammation, cell death, and related processes. Methods. A cross-sectional study was conducted, and clinical data and blood samples were collected from 56 men with central obesity (obese group) and 29 nonobese individuals (control group). Clinical evaluations and predefined biochemical screening tests were performed. The efferocytosis signaling pathway was investigated by measuring phosphatidylserine (PS), ADAM17, TNF-alpha (TNF-α), and sMER. Results. Metabolic syndrome was detected in more than half of the participants in the obese group according to the predefined tests. Mean levels of PS, TNF-α, and sMER were higher in the obese group but not significantly different from those of the control group. Further analysis based on waist circumference (WC) ranges in the obese group revealed a significant increase in PS and sMER levels between the control group and the obese group with WC greater than 120 cm. ADAM17 levels were significantly higher in the obese group than in the control group. PS was positively correlated with WC and ADAM17. ADAM17 was positively correlated with TNF-α and sMER, indicating impaired efferocytosis. Conclusions. Central obesity appeared to cause a disturbance in efferocytosis that began with cell damage and death, along with an enlargement of the WC and an ongoing inflammatory response. Efferocytosis was disrupted by proinflammatory cytokine regulators, which induced the production of sMER and interfered with the efferocytosis process.
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Guo, Linlin, Yangzhen Wang, Xiaodan Qiu, Wenfang Su, Yixuan Chen, and Yuanqing Chen. "Identification of diagnostic biomarkers related to the efferocytosis pathway and immune cell infiltration characteristics in pediatric sepsis by bioinformatics analysis." Medicine 104, no. 6 (February 7, 2025): e41267. https://doi.org/10.1097/md.0000000000041267.
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Pediatric sepsis is a serious disease characterized by multiple organ failure. Due to its unique pathogenesis, its clinical mortality rate is very high. This study systematically evaluated the value of efferocytosis related genes in the diagnosis of sepsis in children. We downloaded gene expression profiles related to pediatric sepsis from the gene expression omnibus database, identify differentially expressed genes (DEGs) by limma R package, and retrieve adult sepsis gene expression profiles to determine the specificity of pediatric sepsis biomarkers. Selected pediatric sepsis specific genes from these profiles and used clusterProfiler for Kyoto Encyclopedia of Genes and Genomes (KEGG), gene ontology, and Reactome databases for functional enrichment. Genesets related to Efferocytosis was searched in the KEGG database, and the intersection with pediatric sepsis specific genes was considered as pediatric sepsis-efferocytosis genes. Immune infiltration analysis was performed using the CIBERSORT package. Constructed a protein–protein interaction (PPI) network and screened for hub genes in pediatric sepsis-efferocytosis genes. Further select diagnostic markers through gene expression and receiver operating characteristic (ROC) curve. We identified a total of 281 DEGs specific to pediatric sepsis, which are enriched in pathways such as phagosome, autophagy and efferocytosis. We found that the efferocytosis pathway is significantly up-regulated in pediatric sepsis, while this pathway is not significant in adult sepsis. We noticed that 12 types of immune cells infiltration levels including macrophages in pediatric sepsis patients. We selected the top 20 hub genes with PPI network. By overlapping hub genes with pediatric sepsis-efferocytosis genes, we obtained 2 hub pediatric sepsis-efferocytosis genes (ALOX5, CD36). The ROC curve suggested that these genes may be potential diagnostic markers for pediatric sepsis. We have identified ALOX5 and CD36 as efferocytosis related genes associated with pediatric sepsis, which can reliably identify pediatric sepsis and provide prospective clinical references for the pathogenesis of pediatric sepsis.
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Zheng, Qian, Ning Gao, Qiling Sun, Xiaowen Li, Yanzhe Wang, and Hui Xiao. "bfc, a novel serpent co-factor for the expression of croquemort, regulates efferocytosis in Drosophila melanogaster." PLOS Genetics 17, no. 12 (December 3, 2021): e1009947. http://dx.doi.org/10.1371/journal.pgen.1009947.
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Efferocytosis is the process by which phagocytes recognize, engulf, and digest (or clear) apoptotic cells during development. Impaired efferocytosis is associated with developmental defects and autoimmune diseases. In Drosophila melanogaster, recognition of apoptotic cells requires phagocyte surface receptors, including the scavenger receptor CD36-related protein, Croquemort (Crq, encoded by crq). In fact, Crq expression is upregulated in the presence of apoptotic cells, as well as in response to excessive apoptosis. Here, we identified a novel gene bfc (booster for croquemort), which plays a role in efferocytosis, specifically the regulation of the crq expression. We found that Bfc protein interacts with the zinc finger domain of the GATA transcription factor Serpent (Srp), to enhance its direct binding to the crq promoter; thus, they function together in regulating crq expression and efferocytosis. Overall, we show that Bfc serves as a Srp co-factor to upregulate the transcription of the crq encoded receptor, and consequently boosts macrophage efferocytosis in response to excessive apoptosis. Therefore, this study clarifies how phagocytes integrate apoptotic cell signals to mediate efferocytosis.
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Das, Dipankar, Harsha Bhattacharjee, Kasturi Bhattacharjee, Prerana S. Tahiliani, Pankaj Bhattacharyya, Manabjyoti Barman, Sumita Sarma Barthakur, Panna Deka, Apurba Deka, and Rajashree Paul. "Efferocytosis in Retinoblastoma." Journal of Cancer Therapy 04, no. 09 (2013): 1443–47. http://dx.doi.org/10.4236/jct.2013.49172.
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Henson, Peter M. "Cell Removal: Efferocytosis." Annual Review of Cell and Developmental Biology 33, no. 1 (October 6, 2017): 127–44. http://dx.doi.org/10.1146/annurev-cellbio-111315-125315.
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Purnama, Chandra Agung, Anna Meiliana, Melisa Intan Barliana, Keri Lestari Dandan, and Andi Wijaya. "Apoptosis and Efferocytosis in Inflammatory Diseases." Indonesian Biomedical Journal 13, no. 3 (September 9, 2021): 242–55. http://dx.doi.org/10.18585/inabj.v13i3.1608.
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BACKGROUND: Millions of cells in multicellular organisms regenerate every day to replace aged and died cells. Effective cell clearance (efferocytosis) is critical for tissue homeostasis, as the human body recycles its cellular components. We summarize what is known about the mechanisms of efferocytosis and how it impacts the physiology of the organism, effects on inflammation and the adaptive immune response, as well as the consequences of defects in this critical homeostatic mechanism in this review.CONTENT: Cell death is the process by which the human body replaces aged or damaged cells with new ones. It can be triggered by genetically encoded machinery or regulated cell death, or by specific pharmacologic or genetic interventions, resulting in accidental cell death. Dying cells release signals that entice phagocytes to engulf them in a process known as efferocytosis. Efferocytosis is a multistep process involving the release of “find me” and “eat me” signals and destruction of death cells by phagocytes. Different types of cell death including apoptosis and necroptosis can express pro- or anti-inflammatory signals via macrophage activity modulation.SUMMARY: Failed or ineffective efferocytosis can result in disruption of tissue homeostasis, which can contribute to the development of chronic inflammatory diseases such as atherosclerosis, obesity, diabetes, and heart failure. Therefore, any therapeutic strategy that enhances efferocytosis will have a beneficial effect on the treatment of these metabolic disorders.KEYWORDS: apoptosis, necroptosis, phagocytosis, efferocytosis, macrophage.
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Anandan, Vinitha, Thushara Thulaseedharan, Aishwarya Suresh Kumar, Karthika Chandran Latha, Amjesh Revikumar, Ajit Mullasari, Chandrasekharan C. Kartha, Abdul Jaleel, and Surya Ramachandran. "Cyclophilin A Impairs Efferocytosis and Accelerates Atherosclerosis by Overexpressing CD 47 and Down-Regulating Calreticulin." Cells 10, no. 12 (December 20, 2021): 3598. http://dx.doi.org/10.3390/cells10123598.
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Impairment of efferocytosis in apoptotic macrophages is a known determinant of the severity of atherosclerosis and the vulnerability of plaques to rupture. The precise mechanisms involved in impaired efferocytosis are unclear. Given the well-recognized role of the inflammatory cytokine cyclophilin A (Cyp A) in modulating several atherogenic mechanisms in high-glucose primed monocytes, we investigated the role of Cyp A in macrophage efferocytosis. The efficiency of efferocytosis in RAW 264.7 macrophages grown in vitro and primed with cyclophilin A was assessed using flow cytometry and confocal assays. Cholesterol content in cells was measured using cell-based cholesterol efflux assay. Proteomic analysis and bioinformatics tools were employed to decipher the link between cyclophilin A and the known ligand receptors involved in efferocytosis. Cyclophilin A was found to impair efferocytosis in apoptotic macrophages by reducing ABCA1-mediated cholesterol efflux in foam cells derived from macrophages. Cyclophilin A-primed macrophages showed an increase in expression of the don’t-eat-me signal CD 47 and a decrease in the expression of the eat-me signal, calreticulin. Phagocytosis was restored upon silencing of cyclophilin A. New Zealand white rabbits were fed a high-fat diet, and lesions in their aortae were analyzed histologically for evidence of atherosclerosis and the expression of Cyp A, CD 47 and calreticulin, the ligand receptor involved in efferocytosis. Gene and protein expressions in aortae and macrophages were analyzed by real-time PCR and Western blotting. Cyclophilin A, via its effects on the expression of CD 47 and calreticulin, impairs efferocytosis in apoptotic macrophages. Together with its impact on cholesterol efflux from macrophages, these effects can amplify other mechanisms of Cyp A in accelerating the progression of atherosclerosis.
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Fige, Éva, Zsolt Sarang, László Sós, and Zsuzsa Szondy. "Retinoids Promote Mouse Bone Marrow-Derived Macrophage Differentiation and Efferocytosis via Upregulating Bone Morphogenetic Protein-2 and Smad3." Cells 11, no. 18 (September 19, 2022): 2928. http://dx.doi.org/10.3390/cells11182928.
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Clearance of apoptotic cells by bone marrow-derived macrophages differentiated from monocytes plays a central role in the resolution of inflammation, as the conversion of pro-inflammatory M1 macrophages to M2 macrophages that mediate the resolution process occurs during efferocytosis. Thus, proper efferocytosis is a prerequisite for proper resolution of inflammation, and failure in efferocytosis is associated with the development of chronic inflammatory diseases. Previous studies from our laboratory have shown that (13R)-all-trans-13,14-dihydroretinol (DHR), the product of retinol saturase, acting from day 4 of monocyte differentiation enhances the efferocytosis capacity of the resulted macrophages. Loss of retinol saturase in mice leads to impaired efferocytosis, and to development of autoimmunity. In the present paper, we report that in differentiating monocytes DHR, retinol, and all-trans retinoic acid all act directly on retinoic acid receptors and enhance the clearance of apoptotic cells by upregulating the expression of several efferocytosis-related genes. The effect of retinoids seems to be mediated by bone morphogenetic protein (BMP)-2, and the Smad3 transcription factor. In addition, retinoids also upregulate the expression of the vitamin D receptor and that of vascular endothelial growth factor A, indicating that altogether retinoids promote the generation of a pro-reparative M2 macrophage population during monocyte differentiation.
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Ferracini, Matheus, Francisco J. O. Rios, Mateus Pecenin, and Sonia Jancar. "Clearance of Apoptotic Cells by Macrophages Induces Regulatory Phenotype and Involves Stimulation of CD36 and Platelet-Activating Factor Receptor." Mediators of Inflammation 2013 (2013): 1–8. http://dx.doi.org/10.1155/2013/950273.
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Phagocytosis of apoptotic cells (efferocytosis) induces macrophage differentiation towards a regulatory phenotype (IL-10high/IL-12p40low). CD36 is involved in the recognition of apoptotic cells (AC), and we have shown that the platelet-activating factor receptor (PAFR) is also involved. Here, we investigated the contribution of PAFR and CD36 to efferocytosis and to the establishment of a regulatory macrophage phenotype. Mice bone marrow-derived macrophages were cocultured with apoptotic thymocytes, and the phagocytic index was determined. Blockage of PAFR with antagonists or CD36 with specific antibodies inhibited the phagocytosis of AC (~70–80%). Using immunoprecipitation and confocal microscopy, we showed that efferocytosis increased the CD36 and PAFR colocalisation in the macrophage plasma membrane; PAFR and CD36 coimmunoprecipitated with flotillin-1, a constitutive lipid raft protein, and disruption of these membrane microdomains by methyl-β-cyclodextrin reduced AC phagocytosis. Efferocytosis induced a pattern of cytokine production, IL-10high/IL-12p40low, that is, characteristic of a regulatory phenotype. LPS potentiated the efferocytosis-induced production of IL-10, and this was prevented by blocking PAFR or CD36. It can be concluded that phagocytosis of apoptotic cells engages CD36 and PAFR, possibly in lipid rafts, and this is required for optimal efferocytosis and the establishment of the macrophage regulatory phenotype.
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Fernandez-Boyanapalli, Ruby F., S. Courtney Frasch, Kathleen McPhillips, R. William Vandivier, Brian L. Harry, David W. H. Riches, Peter M. Henson, and Donna L. Bratton. "Impaired apoptotic cell clearance in CGD due to altered macrophage programming is reversed by phosphatidylserine-dependent production of IL-4." Blood 113, no. 9 (February 26, 2009): 2047–55. http://dx.doi.org/10.1182/blood-2008-05-160564.
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Chronic granulomatous disease (CGD) is characterized by overexuberant inflammation and autoimmunity that are attributed to deficient anti-inflammatory signaling. Although regulation of these processes is complex, phosphatidylserine (PS)–dependent recognition and removal of apoptotic cells (efferocytosis) by phagocytes are potently anti-inflammatory. Since macrophage phenotype also plays a beneficial role in resolution of inflammation, we hypothesized that impaired efferocytosis in CGD due to macrophage skewing contributes to enhanced inflammation. Here we demonstrate that efferocytosis by macrophages from CGD (gp91phox−/−) mice was suppressed ex vivo and in vivo. Alternative activation with interleukin 4 (IL-4) normalized CGD macrophage efferocytosis, whereas classical activation by lipopolysaccharide (LPS) plus interferon γ (IFNγ) had no effect. Importantly, neutralization of IL-4 in wild-type macrophages reduced macrophage efferocytosis, demonstrating a central role for IL-4. This effect was shown to involve 12/15 lipoxygenase and activation of peroxisome-proliferator activated receptor γ (PPARγ). Finally, injection of PS (whose exposure is lacking on CGD apoptotic neutrophils) in vivo restored IL-4–dependent macrophage reprogramming and efferocytosis via a similar mechanism. Taken together, these findings support the hypothesis that impaired PS exposure on dying cells results in defective macrophage programming, with consequent efferocytic impairment and has important implications in understanding the underlying cause of enhanced inflammation in CGD.
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Yoshida, S., N. Minematsu, S. Chubachi, H. Nakamura, M. Miyazaki, K. Tsuduki, S. Takahashi, et al. "Annexin V decreases PS-mediated macrophage efferocytosis and deteriorates elastase-induced pulmonary emphysema in mice." American Journal of Physiology-Lung Cellular and Molecular Physiology 303, no. 10 (November 15, 2012): L852—L860. http://dx.doi.org/10.1152/ajplung.00066.2012.
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Efferocytosis is believed to be a key regulator for lung inflammation in chronic obstructive pulmonary disease. In this study we pharmacologically inhibited efferocytosis with annexin V and attempted to determine its impact on the progression of pulmonary emphysema in mouse. We first demonstrated in vitro and in vivo efferocytosis experiments using annexin V, an inhibitor for phosphatidylserine-mediated efferocytosis. We then inhibited efferocytosis in porcine pancreatic elastase (PPE)-treated mice. PPE-treated mice were instilled annexin V intranasally starting from day 8 until day 20. Mean linear intercept (Lm) was measured, and cell apoptosis was assessed in lung specimen obtained on day 21. Cell profile, apoptosis, and mRNA expression of matrix metalloproteinases (MMPs) and growth factors were evaluated in bronchoalveolar lavage (BAL) cells on day 15. Annexin V attenuated macrophage efferocytosis both in vitro and in vivo. PPE-treated mice had a significant higher Lm, and annexin V further increased that by 32%. More number of macrophages was found in BAL fluid in this group. Interestingly, cell apoptosis was not increased by annexin V treatment both in lung specimens and BAL fluid, but macrophages from mice treated with both PPE and annexin V expressed higher MMP-2 mRNA levels and had a trend for higher MMP-12 mRNA expression. mRNA expression of keratinocyte growth factor tended to be downregulated. We showed that inhibited efferocytosis with annexin V worsened elastase-induced pulmonary emphysema in mice, which was, at least partly, attributed to a lack of phenotypic change in macrophages toward anti-inflammatory one.
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Zhang, Yan, Ying Wang, Dong Zhou, Li-Sha Zhang, Fu-Xue Deng, Shan Shu, Li-Jun Wang, et al. "Angiotensin II deteriorates advanced atherosclerosis by promoting MerTK cleavage and impairing efferocytosis through the AT1R/ROS/p38 MAPK/ADAM17 pathway." American Journal of Physiology-Cell Physiology 317, no. 4 (October 1, 2019): C776—C787. http://dx.doi.org/10.1152/ajpcell.00145.2019.
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Vulnerable plaques in advanced atherosclerosis have defective efferocytosis. The role of ANG II in the progression of atherosclerosis is not fully understood. Herein, we investigated the effects and the underlying mechanisms of ANG II on macrophage efferocytosis in advanced atherosclerosis. ANG II decreased the surface expression of Mer tyrosine kinase (MerTK) in macrophages through a disintegrin and metalloproteinase17 (ADAM17)-mediated shedding of the soluble form of MerTK (sMer) in the medium, which led to efferocytosis suppression. ANG II-activated ADAM17 required reactive oxygen species (ROS) and p38 MAPK phosphorylation. Selective angiotensin II type 1 receptor (AT1R) blocker losartan suppressed ROS production, and ROS scavenger N-acetyl-l-cysteine (NAC) prevented p38 MAPK phosphorylation. In addition, mutant MERTKΔ483-488 was resistant to ANG II-induced MerTK shedding and efferocytosis suppression. The advanced atherosclerosis model that is characterized by larger necrotic cores, and less collagen content was established by feeding apolipoprotein E knockout (ApoE−/−) mice with a high-fat diet for 16 wk. NAC and losartan oral administration prevented atherosclerotic lesion progression. Meanwhile, the inefficient efferocytosis represented by decreased macrophage-associated apoptotic cells and decreased MerTK+CD68+double-positive macrophages in advanced atherosclerosis were prevented by losartan and NAC. Additionally, the serum levels of sMer were increased and positively correlated with the upregulated levels of ANG II in acute coronary syndrome (ACS) patients. In conclusion, ANG II promotes MerTK shedding via AT1R/ROS/p38 MAPK/ADAM17 pathway in macrophages, which led to defective efferocytosis and atherosclerosis progression. Defining the molecular mechanisms of defective efferocytosis may provide a promising prognosis and therapy for ACS patients.
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Tsay, Gregory J., Fei-Hung Hsieh, Ting-Yin Xue, Hsin-Yi Peng, Yan-Chi Tsao, Mei-Chin Yin, Jiunn-Horng Chen, Chung-Ming Huang, Der-Yuan Chen, and Joung-Liang Lan. "Hydroxychloroquine enhances efferocytosis and inhibits IL-6 and TNF-α productions through upregulating both Gas6/Axl and MFG-E8/TG2 Signaling pathways in Pristine-induced lupus mice." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 236.18. http://dx.doi.org/10.4049/jimmunol.204.supp.236.18.
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Abstract Objectives Impaired clearance of apoptotic cells (efferocytosis) plays an important role in the pathogenesis of autoimmune diseases, especially systemic lupus erythematosus (SLE). Hydroxychloroquine (HCQ) has been widely used to treat autoimmune diseases. We aimed to investigate the underlying mechanism of efferocytosis in the action of HCQ. Methods Eighteen 6-week-old female BALB/c mice were treated Intraperitoneally with pristine in Pristine-induced lupus mice (PIL). Efferocytosis was performed using mouse cell lines EL4 as apoptotic cells and co-cultured with RAW 264.7 and peritoneal macrophages of PIL to investigate the effect of HCQ on efferocytosis which was analyzed with fluorescent microscopy and flow cytometry. Real time PCR was performed to investigate molecular mRNA expressions of signalling pathways. Protein level was measured by ELISA. Results HCQ could enhance efferocytosis with dose-dependent manner in both RAW264.7 cell lines and peritoneal macrophages of PIL with increased expression of GAS6 and MFG-E8 signallings. Both Gas6/Axl and MFG-E8/TG2 Signalling pathways play important roles in HCQ-enhanced efferocytosis. In HCQ-treated mice of PIL, HCQ reduced of IL-6 (p<0.0036) and TNF-α (p<0.06) protein levels in their ascites. Conclusions Our study shows that HCQ can enhance efferocytosis through both Gas6/Axl and MFG-E8/TG2 Signalling pathways and suppress the production of IL-6 and TNF-α. Our findings provide novel insights into understanding the mechanisms of HCQ, which could have the long-term beneficial effects on the therapy of SLE.
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Tsay, Gregory J. "Resveratrol increases efferocytosis via both Mertk-GAS6/PROS and Integrin-TG2-Mfge8 pathway." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 176.9. http://dx.doi.org/10.4049/jimmunol.200.supp.176.9.
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Abstract The impairment of clearance of apoptotic cells (efferocytosis) leads to local inflammatory response and tissue damage. Recent studies have found the defective mechanism in apoptotic clearance is related to the pathogenesis of autoimmune disease such as systemic lupus erythematosus (SLE). There have been many studies about the positive effects of resveratrol, including anti-diabetic effect, anti-inflammation, anti-oxidation, and anti-aging. However, the effect of resveratrol on clearance of apoptotic cells by macrophage is still remaining unknown. We investigated the effects of resveratrol on efferocytosis. Methods HaCaT and the thymocytes from C57BL/6 were induced apoptosis by UVB and stained with Deep red mitotracker. CFSE stained RAW 264.7 was treated with 1, 5, 10 mM resveratrol for 24 hrs then co-cultured with apoptotic HaCaT to investigate the effect of resveratrol on efferocytosis. To measure the mRNA expression, RAW 264.7 RNA was extracted by RNAzol and then progress reverse transcription and real time PCR. Results The results showed that 10 mM resveratrol increased efferocytosis. We further investigated the molecular mechanism of efferocytosis. We found that ITGa5, ITGb3, TG2, Mfge8, and Mertk mRNA were up-regulated by resveratrol after co-cultured with or without apoptotic HaCaT; GAS6 and PROS mRNA expression were up-regulated by resveratrol only after co-cultured with apoptotic cells. The results revealed that resveratrol might enhance efferocytosis by regulating Mfge8-Integrin and GAS6/PROS-Mertk signaling pathway. Conclusion Resveratrol enhances efferocytosis via both Mertk-GAS6/PROS and Integrin-TG2-Mfge8 pathway. Resveratrol may be used for the therapy of autoimmune diseases.
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Schrodt, Michael V., Riley M. Behan-Bush, Jesse N. Liszewski, Madeleine E. Humpal-Pash, Lauren K. Boland, Sabrina M. Scroggins, Donna A. Santillan, and James A. Ankrum. "Efferocytosis of viable versus heat-inactivated MSC induces human monocytes to distinct immunosuppressive phenotypes." Stem Cell Research & Therapy 14, no. 1 (August 17, 2023). http://dx.doi.org/10.1186/s13287-023-03443-z.
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Abstract Background Immunomodulation by mesenchymal stromal cells (MSCs) can occur through trophic factor mechanisms, however, intravenously infused MSCs are rapidly cleared from the body yet a potent immunotherapeutic response is still observed. Recent work suggests that monocytes contribute to the clearance of MSCs via efferocytosis, the body’s natural mechanism for clearing dead and dying cells in a non-inflammatory manner. This begs the questions of how variations in MSC quality affect monocyte phenotype and if viable MSCs are even needed to elicit an immunosuppressive response. Methods Herein, we sought to dissect MSC’s trophic mechanism from their efferocytic mechanisms and determine if the viability of MSCs prior to efferocytosis influences the resultant phenotype of monocytes. We cultured viable or heat-inactivated human umbilical cord MSCs with human peripheral blood mononuclear cells for 24 h and observed changes in monocyte surface marker expression and secretion profile. To isolate the effect of efferocytosis from MSC trophic factors, we used cell separation techniques to remove non-efferocytosed MSCs before challenging monocytes to suppress T-cells or respond to inflammatory stimuli. For all experiments, viable and heat-inactivated efferocytic-licensing of monocytes were compared to non-efferocytic-licensing control. Results We found that monocytes efferocytose viable and heat-inactivated MSCs equally, but only viable MSC-licensed monocytes suppress activated T-cells and suppression occurred even after depletion of residual MSCs. This provides direct evidence that monocytes that efferocytose viable MSCs are immunosuppressive. Further characterization of monocytes after efferocytosis showed that uptake of viable-but not heat inactivated-MSC resulted in monocytes secreting IL-10 and producing kynurenine. When monocytes were challenged with LPS, IL-2, and IFN-γ to simulate sepsis, monocytes that had efferocytosed viable MSC had higher levels of IDO while monocytes that efferocytosed heat inactivated-MSCs produced the lowest levels of TNF-α. Conclusion Collectively, these studies show that the quality of MSCs efferocytosed by monocytes polarize monocytes toward distinctive immunosuppressive phenotypes and highlights the need to tailor MSC therapies for specific indications.
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Myers Chen, Kayla V., Amber E. de Groot, Sabrina A. Mendez, Mikaela M. Mallin, Sarah R. Amend, and Kenneth J. Pienta. "Targeting MerTK decreases efferocytosis and increases anti-tumor immune infiltrate in prostate cancer." Medical Oncology 40, no. 10 (August 29, 2023). http://dx.doi.org/10.1007/s12032-023-02153-z.
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AbstractThe prostate cancer tumor microenvironment (TME) is comprised of many cell types that can contribute to and influence tumor progression. Some of the most abundant prostate cancer TME cells are macrophages, which can be modeled on a continuous spectrum of M1-like (anti-tumor macrophages) to M2-like (pro-tumor macrophages). A function of M2-like macrophages is efferocytosis, the phagocytosis of apoptotic cells. Based on literature from other models and contexts, efferocytosis further supports the M2-like macrophage phenotype. MerTK is a receptor tyrosine kinase that mediates efferocytosis by binding phosphatidylserine on apoptotic cells. We hypothesize efferocytosis in the prostate cancer TME is a tumor-promoting function of macrophages and that targeting MerTK-mediated efferocytosis will slow prostate cancer growth and promote an anti-tumor immune infiltrate. The aims of this study are to measure efferocytosis of prostate cancer cells by in vitro human M1/M2 macrophage models and assess changes in the M2-like, pro-tumor macrophage phenotype following prostate cancer efferocytosis. Additionally, this study aims to demonstrate that targeting MerTK decreases prostate cancer efferocytosis and promotes an anti-tumor immune infiltrate. We have developed methodology using flow cytometry to quantify efferocytosis of human prostate cancer cells using the LNCaP cell line. We observed that M2 macrophages efferocytose the LNCaP cell line more than M1 macrophages. Following efferocytosis of LNCaP cells by M2 human monocyte-derived macrophages (HMDMs), we observed an increase in the M2-like, pro-tumor phenotype by flow cytometry cell surface marker analysis. By qRT-PCR, flow cytometry, and Western blot, we detected greater MerTK expression in M2 than M1 macrophages. Targeting MerTK with antibody Mer590 decreased LNCaP efferocytosis by M2 HMDMs, establishing the role of MerTK in prostate cancer efferocytosis. In the prostate cancer mouse model hi-myc, Mertk KO increased anti-tumor immune infiltrate including CD8 T cells. These findings support targeting MerTK-mediated efferocytosis as a novel therapy for prostate cancer.
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Lacey, Keenan A., Adam M. Pickrum, Sandra Gonzalez, Eric Bartnicki, Ashley H. Castellaw, Tori C. Rodrick, Drew R. Jones, Kamal M. Khanna, and Victor J. Torres. "Dietary and water restriction leads to increased susceptibility to antimicrobial resistant pathogens." Science Advances 10, no. 30 (July 26, 2024). http://dx.doi.org/10.1126/sciadv.adi7438.
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Dehydration and malnutrition are common and often underdiagnosed in hospital settings. Multidrug-resistant bacterial infections result in more than 35,000 deaths a year in nosocomial patients. The effect of temporal dietary and water restriction (DWR) on susceptibility to multidrug-resistant pathogens is unknown. We report that DWR markedly increased susceptibility to systemic infection by ESKAPE pathogens. Using a murine bloodstream model of methicillin-resistant Staphylococcus aureus infection, we show that DWR leads to significantly increased mortality and morbidity. DWR causes increased bacterial burden, severe pathology, and increased numbers of phagocytes in the kidney. DWR appears to alter the functionality of these phagocytes and is therefore unable to control infection. Mechanistically, we show that DWR impairs the ability of macrophages to phagocytose multiple bacterial pathogens and efferocytose apoptotic neutrophils. Together, this work highlights the crucial impact that diet and hydration play in protecting against infection.
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Zhao, Jiayi, Weiqi Zhang, Tingting Wu, Hongyi Wang, Jialiang Mao, Jian Liu, Ziheng Zhou, Xianfeng Lin, Huige Yan, and Qingqing Wang. "Efferocytosis in the Central Nervous System." Frontiers in Cell and Developmental Biology 9 (December 3, 2021). http://dx.doi.org/10.3389/fcell.2021.773344.
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The effective clearance of apoptotic cells is essential for maintaining central nervous system (CNS) homeostasis and restoring homeostasis after injury. In most cases of physiological apoptotic cell death, efferocytosis prevents inflammation and other pathological conditions. When apoptotic cells are not effectively cleared, destruction of the integrity of the apoptotic cell membrane integrity, leakage of intracellular contents, and secondary necrosis may occur. Efferocytosis is the mechanism by which efferocytes quickly remove apoptotic cells from tissues before they undergo secondary necrosis. Cells with efferocytosis functions, mainly microglia, help to eliminate apoptotic cells from the CNS. Here, we discuss the impacts of efferocytosis on homeostasis, the mechanism of efferocytosis, the associations of efferocytosis failure and CNS diseases, and the current clinical applications of efferocytosis. We also identify efferocytosis as a novel potential target for exploring the causes and treatments of CNS diseases.
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Sheng, Yan−Ran, Wen−Ting Hu, Siman Chen, and Xiao−Yong Zhu. "Efferocytosis by macrophages in physiological and pathological conditions: regulatory pathways and molecular mechanisms." Frontiers in Immunology 15 (May 8, 2024). http://dx.doi.org/10.3389/fimmu.2024.1275203.
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Efferocytosis is defined as the highly effective phagocytic removal of apoptotic cells (ACs) by professional or non-professional phagocytes. Tissue-resident professional phagocytes (“efferocytes”), such as macrophages, have high phagocytic capacity and are crucial to resolve inflammation and aid in homeostasis. Recently, numerous exciting discoveries have revealed divergent (and even diametrically opposite) findings regarding metabolic immune reprogramming associated with efferocytosis by macrophages. In this review, we highlight the key metabolites involved in the three phases of efferocytosis and immune reprogramming of macrophages under physiological and pathological conditions. The next decade is expected to yield further breakthroughs in the regulatory pathways and molecular mechanisms connecting immunological outcomes to metabolic cues as well as avenues for “personalized” therapeutic intervention.
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Yin, Charles, and Bryan Heit. "Cellular Responses to the Efferocytosis of Apoptotic Cells." Frontiers in Immunology 12 (April 20, 2021). http://dx.doi.org/10.3389/fimmu.2021.631714.
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The rapid and efficient phagocytic clearance of apoptotic cells, termed efferocytosis, is a critical mechanism in the maintenance of tissue homeostasis. Removal of apoptotic cells through efferocytosis prevents secondary necrosis and the resultant inflammation caused by the release of intracellular contents. The importance of efferocytosis in homeostasis is underscored by the large number of inflammatory and autoimmune disorders, including atherosclerosis and systemic lupus erythematosus, that are characterized by defective apoptotic cell clearance. Although mechanistically similar to the phagocytic clearance of pathogens, efferocytosis differs from phagocytosis in that it is immunologically silent and induces a tissue repair response. Efferocytes face unique challenges resulting from the internalization of apoptotic cells, including degradation of the apoptotic cell, dealing with the extra metabolic load imposed by the processing of apoptotic cell contents, and the coordination of an anti-inflammatory, pro-tissue repair response. This review will discuss recent advances in our understanding of the cellular response to apoptotic cell uptake, including trafficking of apoptotic cell cargo and antigen presentation, signaling and transcriptional events initiated by efferocytosis, the coordination of an anti-inflammatory response and tissue repair, unique cellular metabolic responses and the role of efferocytosis in host defense. A better understanding of how efferocytic cells respond to apoptotic cell uptake will be critical in unraveling the complex connections between apoptotic cell removal and inflammation resolution and maintenance of tissue homeostasis.
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Sahebi, Keivan, Hassan Foroozand, Mobina Amirsoleymani, Saghi Eslamzadeh, Manica Negahdaripour, Amir Tajbakhsh, Abbas Rahimi Jaberi, and Amir Savardashtaki. "Advancing stroke recovery: unlocking the potential of cellular dynamics in stroke recovery." Cell Death Discovery 10, no. 1 (July 11, 2024). http://dx.doi.org/10.1038/s41420-024-02049-5.
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AbstractStroke stands as a predominant cause of mortality and morbidity worldwide, and there is a pressing need for effective therapies to improve outcomes and enhance the quality of life for stroke survivors. In this line, effective efferocytosis, the clearance of apoptotic cells, plays a crucial role in neuroprotection and immunoregulation. This process involves specialized phagocytes known as “professional phagocytes” and consists of four steps: “Find-Me,” “Eat-Me,” engulfment/digestion, and anti-inflammatory responses. Impaired efferocytosis can lead to secondary necrosis and inflammation, resulting in adverse outcomes following brain pathologies. Enhancing efferocytosis presents a potential avenue for improving post-stroke recovery. Several therapeutic targets have been identified, including osteopontin, cysteinyl leukotriene 2 receptor, the µ opioid receptor antagonist β-funaltrexamine, and PPARγ and RXR agonists. Ferroptosis, defined as iron-dependent cell death, is now emerging as a novel target to attenuate post-stroke tissue damage and neuronal loss. Additionally, several biomarkers, most importantly CD163, may serve as potential biomarkers and therapeutic targets for acute ischemic stroke, aiding in stroke diagnosis and prognosis. Non-pharmacological approaches involve physical rehabilitation, hypoxia, and hypothermia. Mitochondrial dysfunction is now recognized as a major contributor to the poor outcomes of brain stroke, and medications targeting mitochondria may exhibit beneficial effects. These strategies aim to polarize efferocytes toward an anti-inflammatory phenotype, limit the ingestion of distressed but viable neurons, and stimulate efferocytosis in the late phase of stroke to enhance post-stroke recovery. These findings highlight promising directions for future research and development of effective stroke recovery therapies.
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Batoon, Lena, Amy J. Koh, Rahasudha Kannan, Laurie K. McCauley, and Hernan Roca. "Caspase-9 driven murine model of selective cell apoptosis and efferocytosis." Cell Death & Disease 14, no. 1 (January 24, 2023). http://dx.doi.org/10.1038/s41419-023-05594-6.
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AbstractApoptosis and efficient efferocytosis are integral to growth, development, and homeostasis. The heterogeneity of these mechanisms in different cells across distinct tissues renders it difficult to develop broadly applicable in vivo technologies. Here, we introduced a novel inducible caspase-9 (iCasp9) mouse model which allowed targeted cell apoptosis and further facilitated investigation of concomitant efferocytosis. We generated iCasp9+/+ mice with conditional expression of chemically inducible caspase-9 protein that is triggered in the presence of Cre recombinase. In vitro, bone marrow cells from iCasp9+/+ mice showed expression of the iCasp9 protein when transduced with Cre-expressing adenovirus. Treatment of these cells with the chemical dimerizer (AP20187/AP) resulted in iCasp9 processing and cleaved caspase-3 upregulation, indicating successful apoptosis induction. The in vivo functionality and versatility of this model was demonstrated by crossing iCasp9+/+ mice with CD19-Cre and Osteocalcin (OCN)-Cre mice to target CD19+ B cells or OCN+ bone-lining osteoblasts. Immunofluorescence and/or immunohistochemical staining in combination with histomorphometric analysis of EGFP, CD19/OCN, and cleaved caspase-3 expression demonstrated that a single dose of AP effectively induced apoptosis in CD19+ B cells or OCN+ osteoblasts. Examination of the known efferocytes in the target tissues showed that CD19+ cell apoptosis was associated with infiltration of dendritic cells into splenic B cell follicles. In the bone, where efferocytosis remains under-explored, the use of iCasp9 provided direct in vivo evidence that macrophages are important mediators of apoptotic osteoblast clearance. Collectively, this study presented the first mouse model of iCasp9 which achieved selective apoptosis, allowing examination of subsequent efferocytosis. Given its unique feature of being controlled by any Cre-expressing mouse lines, the potential applications of this model are extensive and will bring forth more insights into the diversity of mechanisms and cellular effects induced by apoptosis including the physiologically important efferocytic process that follows.
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Kang, Yoon‐Young, Dong‐Young Kim, Sang‐Yong Lee, Hee‐Joong Kim, Taehawn Kim, Jeong A. Cho, Taewon Lee, and Eun Young Choi. "Innate Immune Training Initiates Efferocytosis to Protect against Lung Injury." Advanced Science, January 26, 2024. http://dx.doi.org/10.1002/advs.202308978.
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AbstractInnate immune training involves myelopoiesis, dynamic gene modulation, and functional reprogramming of myeloid cells in response to secondary heterologous challenges. The present study evaluates whether systemic innate immune training can protect tissues from local injury. Systemic pretreatment of mice with β‐glucan, a trained immunity agonist, reduces the mortality rate of mice with bleomycin‐induced lung injury and fibrosis, as well as decreasing collagen deposition in the lungs. β‐Glucan pretreatment induces neutrophil accumulation in the lungs and enhances efferocytosis. Training of mice with β‐glucan results in histone modification in both alveolar macrophages (AMs) and neighboring lung epithelial cells. Training also increases the production of RvD1 and soluble mediators by AMs and efferocytes. Efferocytosis increases trained immunity in AMs by stimulating RvD1 release, thus inducing SIRT1 expression in neighboring lung epithelial cells. Elevated epithelial SIRT1 expression is associated with decreased epithelial cell apoptosis after lung injury, attenuating tissue damage. Further, neutrophil depletion dampens the effects of β‐glucan on macrophage accumulation, epigenetic modification in lung macrophages, epithelial SIRT1 expression, and injury‐mediated fibrosis in the lung. These findings provide mechanistic insights into innate immune training and clues to the potential ability of centrally trained immunity to protect peripheral organs against injury‐mediated disorders.
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Koenis, Duco Steven, Roberta de Matteis, Vinothini Rajeeve, Pedro Cutillas, and Jesmond Dalli. "Efferocyte‐Derived MCTRs Metabolically Prime Macrophages for Continual Efferocytosis via Rac1‐Mediated Activation of Glycolysis." Advanced Science, December 8, 2023. http://dx.doi.org/10.1002/advs.202304690.
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AbstractClearance of multiple rounds of apoptotic cells (ACs) through continual efferocytosis is critical in the maintenance of organ function, the resolution of acute inflammation, and tissue repair. To date, little is known about the nature of mechanisms and factors that govern this fundamental process. Herein, the authors reported that breakdown of ACs leads to upregulation of 12‐lipoxygenase in macrophages. This enzyme converts docosahexaenoic acid to maresin conjugates in tissue regeneration (MCTRs). The levels of these autacoids are elevated at sites of high apoptotic burden in vivo and in efferocytosing macrophages in vitro. Abrogation of MCTR production using genetic approaches limits the ability of macrophages to perform continual efferocytosis both in vivo and in vitro, an effect that is rescued by add‐back of MCTRs. Mechanistically, MCTR‐mediated priming of macrophages for continual efferocytosis is dependent on alterations in Rac1 signalling and glycolytic metabolism. Inhibition of Rac1 abolishes the ability of MCTRs to increase glucose uptake and efferocytosis in vitro, whereas inhibition of glycolysis limits the MCTR‐mediated increases in efferocytosis and tissue repair. Together, these findings demonstrate that upregulation of MCTRs by efferocytosing macrophages plays a central role in the regulation of continual efferocytosis via the autocrine and paracrine modulation of metabolic pathways.
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Singh, Bandana, Kathryn Li, Kui Cui, Qianman Peng, Douglas B. Cowan, Da-Zhi Wang, Kaifu Chen, and Hong Chen. "Defective efferocytosis of vascular cells in heart disease." Frontiers in Cardiovascular Medicine 9 (September 30, 2022). http://dx.doi.org/10.3389/fcvm.2022.1031293.
Full textAbstract:
The efficient phagocytic clearance of dying cells and apoptotic cells is one of the processes that is essential for the maintenance of physiologic tissue function and homeostasis, which is termed “efferocytosis.” Under normal conditions, “find me” and “eat me” signals are released by apoptotic cells to stimulate the engulfment and efferocytosis of apoptotic cells. In contrast, abnormal efferocytosis is related to chronic and non-resolving inflammatory diseases such as atherosclerosis. In the initial steps of atherosclerotic lesion development, monocyte-derived macrophages display efficient efferocytosis that restricts plaque progression; however, this capacity is reduced in more advanced lesions. Macrophage reprogramming as a result of the accumulation of apoptotic cells and augmented inflammation accounts for this diminishment of efferocytosis. Furthermore, defective efferocytosis plays an important role in necrotic core formation, which triggers plaque rupture and acute thrombotic cardiovascular events. Recent publications have focused on the essential role of macrophage efferocytosis in cardiac pathophysiology and have pointed toward new therapeutic strategies to modulate macrophage efferocytosis for cardiac tissue repair. In this review, we discuss the molecular and cellular mechanisms that regulate efferocytosis in vascular cells, including macrophages and other phagocytic cells and detail how efferocytosis-related molecules contribute to the maintenance of vascular hemostasis and how defective efferocytosis leads to the formation and progression of atherosclerotic plaques.
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Zhao, Xiao-Hu, Ting Yang, Meng-Yao Zheng, Peinan Zhao, Li-Ya An, Yu-Xing Qi, Ke-Qian Yi, Peng-Cheng Zhang, and Da-Li Sun. "Cystathionine gamma-lyase (Cth) induces efferocytosis in macrophages via ERK1/2 to modulate intestinal barrier repair." Cell Communication and Signaling 21, no. 1 (January 23, 2023). http://dx.doi.org/10.1186/s12964-022-01030-y.
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Abstract Background The inflammatory response induced by intestinal ischaemia‒reperfusion injury (I/R) is closely associated with infectious complications and mortality in critically ill patients, and the timely and effective clearance of apoptotic cells is an important part of reducing the inflammatory response. Studies have shown that the efferocytosis by phagocytes plays an important role. Recently, studies using small intestine organoid models showed that macrophage efferocytosis could promote the repair capacity of the intestinal epithelium. However, no studies have reported efferocytosis in the repair of I/R in animal models. Results We used an in vivo efferocytosis assay and discovered that macrophage efferocytosis played an indispensable role in repairing and maintaining intestinal barrier function after I/R. In addition, the specific molecular mechanism that induced macrophage efferocytosis was Cth-ERK1/2 dependent. We found that Cth drove macrophage efferocytosis in vivo and in vitro. Overexpression/silencing Cth promoted/inhibited the ERK1/2 pathway, respectively, which in turn affected efferocytosis and mediated intestinal barrier recovery. In addition, we found that the levels of Cth and macrophage efferocytosis were positively correlated with the recovery of intestinal function in clinical patients. Conclusion Cth can activate the ERK1/2 signalling pathway, induce macrophage efferocytosis, and thus promote intestinal barrier repair.
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Jamalvandi, Mona, Sayyed Saeid Khayyatzadeh, Mohammad Javad Hayati, and Seyed Mohammad Gheibihayat. "The role of fat‐soluble vitamins in efferocytosis." Cell Biochemistry and Function 42, no. 2 (March 2024). http://dx.doi.org/10.1002/cbf.3972.
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AbstractCell death and the efficient removal of dead cells are two basic mechanisms that maintain homeostasis in multicellular organisms. efferocytosis, which includes four steps recruitment, recognition, binding and signaling, and engulfment. Effectively and quickly removes apoptotic cells from the body. Any alteration in efferocytosis can lead to several diseases, including autoimmune and inflammatory conditions, atherosclerosis, and cancer. A wide range of dietary components affects apoptosis and, subsequently, efferocytosis. Some vitamins, including fat‐soluble vitamins, affect different stages of efferocytosis. Among other things, by affecting macrophages, they are effective in the apoptotic cleansing of cells. Also, polyphenols indirectly intervene in efferocytosis through their effect on apoptosis. Considering that there are limited articles on the effect of nutrition on efferocytosis, in this article we will examine the effect of some dietary components on efferocytosis.
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Bravo, Daniel D., Yongchang Shi, Allison Sheu, Wei-Ching Liang, WeiYu Lin, Yan Wu, Minhong Yan, and Jianyong Wang. "A Real-Time Image-Based Efferocytosis Assay for the Discovery of Functionally Inhibitory Anti-MerTK Antibodies." Journal of Immunology, March 1, 2023. http://dx.doi.org/10.4049/jimmunol.2200597.
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Abstract Efferocytosis is a phagocytic process by which apoptotic cells are cleared by professional and nonprofessional phagocytic cells. In tumors, efferocytosis of apoptotic cancer cells by tumor-associated macrophages prevents Ag presentation and suppresses the host immune response against the tumor. Therefore, reactivating the immune response by blockade of tumor-associated macrophage–mediated efferocytosis is an attractive strategy for cancer immunotherapy. Even though several methods have been developed to monitor efferocytosis, an automated and high-throughput quantitative assay should offer highly desirable advantages for drug discovery. In this study, we describe a real-time efferocytosis assay with an imaging system for live-cell analysis. Using this assay, we successfully discovered potent anti-MerTK Abs that block tumor-associated macrophage–mediated efferocytosis in mice. Furthermore, we used primary human and cynomolgus monkey macrophages to identify and characterize anti-MerTK Abs for potential clinical development. By studying the phagocytic activities of different types of macrophages, we demonstrated that our efferocytosis assay is robust for screening and characterization of drug candidates that inhibit unwanted efferocytosis. Moreover, our assay is also applicable to investigating the kinetics and molecular mechanisms of efferocytosis/phagocytosis.
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Ge, Yun, Man Huang, and Yong-ming Yao. "Efferocytosis and Its Role in Inflammatory Disorders." Frontiers in Cell and Developmental Biology 10 (February 25, 2022). http://dx.doi.org/10.3389/fcell.2022.839248.
Full textAbstract:
Efferocytosis is the effective clearance of apoptotic cells by professional and non-professional phagocytes. The process is mechanically different from other forms of phagocytosis and involves the localization, binding, internalization, and degradation of apoptotic cells. Defective efferocytosis has been demonstrated to associate with the pathogenesis of various inflammatory disorders. In the current review, we summarize recent findings with regard to efferocytosis networks and discuss the relationship between efferocytosis and different immune cell populations, as well as describe how efferocytosis helps resolve inflammatory response and modulate immune balance. Our knowledge so far about efferocytosis suggests that it may be a useful target in the treatment of numerous inflammatory diseases.