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1
Inoue, Makoto, and Mari L. Shinohara. "NLRP3 Inflammasome and MS/EAE." Autoimmune Diseases 2013 (2013): 1–8. http://dx.doi.org/10.1155/2013/859145.
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Inflammasomes are cytosolic sensors that detect pathogens and danger signals in the innate immune system. The NLRP3 inflammasome is currently the most fully characterized inflammasome and is known to detect a wide array of microbes and endogenous damage-associated molecules. Possible involvement of the NLRP3 inflammasome (or inflammasomes) in the development of multiple sclerosis (MS) was suggested in a number of studies. Recent studies showed that the NLRP3 inflammasome exacerbates experimental autoimmune encephalomyelitis (EAE), an animal model of MS, although EAE can also develop without the NLRP3 inflammasome. In this paper, we discuss the NLRP3 inflammasome in MS and EAE development.
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Wagatsuma, Kohei, and Hiroshi Nakase. "Contradictory Effects of NLRP3 Inflammasome Regulatory Mechanisms in Colitis." International Journal of Molecular Sciences 21, no. 21 (October 30, 2020): 8145. http://dx.doi.org/10.3390/ijms21218145.
Full textAbstract:
The inflammasome is an intracellular molecular complex, which is mainly involved in innate immunity. Inflammasomes are formed in response to danger signals, associated with infection and injury, and mainly regulate the secretion of interleukin-1β and interleukin-18. Inflammasome dysregulation is known to be associated with various diseases and conditions, and its regulatory mechanisms have become of great interest in recent years. In the colon, inflammasomes have been reported to be associated with autophagy and the microbiota, and their dysregulation contributes to colitis and. However, the detailed role of inflammasomes in inflammatory bowel disease is still under debate because the mechanisms that regulate the inflammasome are complex and the inflammasome components and cytokines show seemingly contradictory multiple effects. Herein, we comprehensively review the literature on inflammasome functioning in the colon and describe the complex interactions of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome components with inflammatory cytokines, autophagy, and the microbiota in experimental colitis models and patients with inflammatory bowel disease.
3
Spalinger, Marianne R., Marlene Schwarzfischer, and Michael Scharl. "The Role of Protein Tyrosine Phosphatases in Inflammasome Activation." International Journal of Molecular Sciences 21, no. 15 (July 31, 2020): 5481. http://dx.doi.org/10.3390/ijms21155481.
Full textAbstract:
Inflammasomes are multi-protein complexes that mediate the activation and secretion of the inflammatory cytokines IL-1β and IL-18. More than half a decade ago, it has been shown that the inflammasome adaptor molecule, ASC requires tyrosine phosphorylation to allow effective inflammasome assembly and sustained IL-1β/IL-18 release. This finding provided evidence that the tyrosine phosphorylation status of inflammasome components affects inflammasome assembly and that inflammasomes are subjected to regulation via kinases and phosphatases. In the subsequent years, it was reported that activation of the inflammasome receptor molecule, NLRP3, is modulated via tyrosine phosphorylation as well, and that NLRP3 de-phosphorylation at specific tyrosine residues was required for inflammasome assembly and sustained IL-1β/IL-18 release. These findings demonstrated the importance of tyrosine phosphorylation as a key modulator of inflammasome activity. Following these initial reports, additional work elucidated that the activity of several inflammasome components is dictated via their phosphorylation status. Particularly, the action of specific tyrosine kinases and phosphatases are of critical importance for the regulation of inflammasome assembly and activity. By summarizing the currently available literature on the interaction of tyrosine phosphatases with inflammasome components we here provide an overview how tyrosine phosphatases affect the activation status of inflammasomes.
4
Forn-Cuní, Gabriel, Annemarie H. Meijer, and Monica Varela. "Zebrafish in Inflammasome Research." Cells 8, no. 8 (August 15, 2019): 901. http://dx.doi.org/10.3390/cells8080901.
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Inflammasomes are cytosolic multiprotein complexes that regulate inflammatory responses to danger stimuli and infection, and their dysregulation is associated with an increasing number of autoinflammatory diseases. In recent years, zebrafish models of human pathologies to study inflammasome function in vivo have started to emerge. Here, we discuss inflammasome research in zebrafish in light of current knowledge about mammalian inflammasomes. We summarize the evolutionary conservation of inflammasome components between zebrafish and mammals, highlighting the similarities and possible divergence in functions of these components. We present new insights into the evolution of the caspase-1 family in the teleost lineage, and how its evolutionary origin may help contextualize its functions. We also review existing infectious and non-infectious models in zebrafish in which inflammasomes have been directly implicated. Finally, we discuss the advantages of zebrafish larvae for intravital imaging of inflammasome activation and summarize available tools that will help to advance inflammasome research.
5
Yi, Young-Su. "Caspase-11 Non-Canonical Inflammasome: Emerging Activator and Regulator of Infection-Mediated Inflammatory Responses." International Journal of Molecular Sciences 21, no. 8 (April 15, 2020): 2736. http://dx.doi.org/10.3390/ijms21082736.
Full textAbstract:
Inflammation is a body’s protective mechanism to eliminate invading pathogens and cellular damaging signals. The inflammatory response consists of two main consecutive steps—a priming step preparing the inflammatory responses and a triggering step boosting the inflammatory responses. The main feature of the triggering step is the activation of the inflammasome, an intracellular multiprotein complex facilitating the inflammatory responses. The regulatory roles of ‘canonical’ inflammasomes in the inflammatory responses and diseases have been largely investigated, so far. New types of inflammasomes have been recently discovered and named as ‘non-canonical’ inflammasomes since their roles to induce inflammatory responses are similar to those of canonical inflammasomes, however, the stimulating ligands and the underlying mechanisms are different. Therefore, a growing number of studies have actively investigated the novel roles of non-canonical inflammasomes in inflammatory responses and diseases. This review summarizes and discusses the recent studies exploring the regulatory roles of caspase-11 non-canonical inflammasome during the inflammatory responses and provides insight into the development of novel therapeutics for infectious and inflammatory diseases by targeting caspase-11 non-canonical inflammasome.
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Looi, Chin King, Ling-Wei Hii, Felicia Fei-Lei Chung, Chun-Wai Mai, Wei-Meng Lim, and Chee-Onn Leong. "Roles of Inflammasomes in Epstein–Barr Virus-Associated Nasopharyngeal Cancer." Cancers 13, no. 8 (April 8, 2021): 1786. http://dx.doi.org/10.3390/cancers13081786.
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Epstein–Barr virus (EBV) infection is recognised as one of the causative agents in most nasopharyngeal carcinoma (NPC) cases. Expression of EBV viral antigens can induce host’s antiviral immune response by activating the inflammasomes to produce pro-inflammatory cytokines, such as interleukin-1β (IL-1β) and IL-18. These cytokines are known to be detrimental to a wide range of virus-infected cells, in which they can activate an inflammatory cell death program, called pyroptosis. However, aberrant inflammasome activation and production of its downstream cytokines lead to chronic inflammation that may contribute to various diseases, including NPC. In this review, we summarise the roles of inflammasomes during viral infection, how EBV evades inflammasome-mediated immune response, and progress into tumourigenesis. The contrasting roles of inflammasomes in cancer, as well as the current therapeutic approaches used in targeting inflammasomes, are also discussed in this review. While the inflammasomes appear to have dual roles in carcinogenesis, there are still many questions that remain unanswered. In particular, the exact molecular mechanism responsible for the regulation of the inflammasomes during carcinogenesis of EBV-associated NPC has not been explored thoroughly. Furthermore, the current practical application of inflammasome inhibitors is limited to specific tumour types, hence, further studies are warranted to discover the potential of targeting the inflammasomes for the treatment of NPC.
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Ball, Daniel P., Cornelius Y. Taabazuing, Andrew R. Griswold, Elizabeth L. Orth, Sahana D. Rao, Ilana B. Kotliar, Lauren E. Vostal, Darren C. Johnson, and Daniel A. Bachovchin. "Caspase-1 interdomain linker cleavage is required for pyroptosis." Life Science Alliance 3, no. 3 (February 12, 2020): e202000664. http://dx.doi.org/10.26508/lsa.202000664.
Full textAbstract:
Pathogen-related signals induce a number of cytosolic pattern-recognition receptors (PRRs) to form canonical inflammasomes, which activate pro-caspase-1 and trigger pyroptotic cell death. All well-studied inflammasome-forming PRRs oligomerize with the adapter protein ASC (apoptosis-associated speck-like protein containing a CARD) to generate a large structure in the cytosol, which induces the dimerization, autoproteolysis, and activation of the pro-caspase-1 zymogen. However, several PRRs can also directly interact with pro-caspase-1 without ASC, forming smaller “ASC-independent” inflammasomes. It is currently thought that little, if any, pro-caspase-1 autoproteolysis occurs during, and is not required for, ASC-independent inflammasome signaling. Here, we show that the related human PRRs NLRP1 and CARD8 exclusively form ASC-dependent and ASC-independent inflammasomes, respectively, identifying CARD8 as the first canonical inflammasome-forming PRR that does not form an ASC-containing signaling platform. Despite their different structures, we discovered that both the NLRP1 and CARD8 inflammasomes require pro-caspase-1 autoproteolysis between the small and large catalytic subunits to induce pyroptosis. Thus, pro-caspase-1 self-cleavage is a required regulatory step for pyroptosis induced by human canonical inflammasomes.
8
Zhang, Zhirong, Gergö Meszaros, Wan-ting He, Yanfang Xu, Helena de Fatima Magliarelli, Laurent Mailly, Michael Mihlan, et al. "Protein kinase D at the Golgi controls NLRP3 inflammasome activation." Journal of Experimental Medicine 214, no. 9 (July 17, 2017): 2671–93. http://dx.doi.org/10.1084/jem.20162040.
Full textAbstract:
The inflammasomes are multiprotein complexes sensing tissue damage and infectious agents to initiate innate immune responses. Different inflammasomes containing distinct sensor molecules exist. The NLRP3 inflammasome is unique as it detects a variety of danger signals. It has been reported that NLRP3 is recruited to mitochondria-associated endoplasmic reticulum membranes (MAMs) and is activated by MAM-derived effectors. Here, we show that in response to inflammasome activators, MAMs localize adjacent to Golgi membranes. Diacylglycerol (DAG) at the Golgi rapidly increases, recruiting protein kinase D (PKD), a key effector of DAG. Upon PKD inactivation, self-oligomerized NLRP3 is retained at MAMs adjacent to Golgi, blocking assembly of the active inflammasome. Importantly, phosphorylation of NLRP3 by PKD at the Golgi is sufficient to release NLRP3 from MAMs, resulting in assembly of the active inflammasome. Moreover, PKD inhibition prevents inflammasome autoactivation in peripheral blood mononuclear cells from patients carrying NLRP3 mutations. Hence, Golgi-mediated PKD signaling is required and sufficient for NLRP3 inflammasome activation.
9
Yang, Qingrui, Chengcheng Yu, Zhaowen Yang, Qing Wei, Kun Mu, Ying Zhang, Wei Zhao, Xiaofeng Wang, Wanwan Huai, and Lihui Han. "Deregulated NLRP3 and NLRP1 Inflammasomes and Their Correlations with Disease Activity in Systemic Lupus Erythematosus." Journal of Rheumatology 41, no. 3 (December 15, 2013): 444–52. http://dx.doi.org/10.3899/jrheum.130310.
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Objective.NOD-like receptor family, pyrin domain containing 3 and 1 (NLRP3 and NLRP1) inflammasomes are molecular platforms that sense the damage or danger signals of cells. We investigated whether NLRP3/NLRP1 inflammasomes are involved in the pathogenesis and progression of systemic lupus erythematosus (SLE).Methods.Expressions of inflammasome components at the mRNA and protein levels in the peripheral blood mononuclear cells (PBMC) from patients with SLE and healthy controls were investigated by quantitative real-time transcription PCR and Western blot, respectively. Correlations between NLRP3/NLRP1 inflammasome components’ expression and clinical disease progression were investigated. Expressions of NLRP3/NLRP1 inflammasomes before and after treatment in the patients with SLE were also analyzed and compared.Results.Our data showed that expressions of NLRP3/NLRP1 inflammasomes were significantly downregulated in PBMC from patients with SLE compared with PBMC from healthy controls. Further, expressions of NLRP3/NLRP1 inflammasomes were negatively correlated with the SLE Disease Activity Index, and regular glucocorticoid treatment significantly corrected this deregulation of these inflammasomes. Further analysis showed that type I interferon (IFN) level was significantly negatively correlated with expression of NLRP3/NLRP1 inflammasomes, which indicated that enhanced IFN-I level in patients with SLE was responsible, at least to a great degree, for the deregulation of inflammasomes.Conclusion.These results indicated deregulation of NLRP3/NLRP1 inflammasomes in patients with SLE, and suggested an important role for inflammasomes in the pathogenesis and progression of SLE.
10
Nourbakhsh, Fahimeh, Morgayn I. Read, George E. Barreto, and Amirhossein Sahebkar. "Astrocytes and Inflammasome: A Possible Crosstalk in Neurological Diseases." Current Medicinal Chemistry 28, no. 24 (August 13, 2021): 4972–94. http://dx.doi.org/10.2174/0929867328666210301105422.
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Inflammasome research has primarily focused on neurological tissue, particularly on damaged tissue. Most current neurological literature involves in vivo and in vitro studies utilizing astroglia, as astroglia express the cytoskeletal glial fibrillary acidic protein (GFAP), which is used as a hallmark of neuropathological disorders. Research suggests that astrocytes respond to all forms of neurological damage or disease through reactive astrogliosis. Additionally, there is a consensus among scientists that inflammasomes play an important role in neuroinflammation. This review focuses on the latest developments in inflammasome biology, describing the current understanding of how inflammasomes can be triggered in the brain and summarizing the literature on the relevance of inflammasome NLR in prevalent neurological diseases.
11
Di Micco, Antonia, Gianluca Frera, Jérôme Lugrin, Yvan Jamilloux, Erh-Ting Hsu, Aubry Tardivel, Aude De Gassart, et al. "AIM2 inflammasome is activated by pharmacological disruption of nuclear envelope integrity." Proceedings of the National Academy of Sciences 113, no. 32 (July 26, 2016): E4671—E4680. http://dx.doi.org/10.1073/pnas.1602419113.
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Inflammasomes are critical sensors that convey cellular stress and pathogen presence to the immune system by activating inflammatory caspases and cytokines such as IL-1β. The nature of endogenous stress signals that activate inflammasomes remains unclear. Here we show that an inhibitor of the HIV aspartyl protease, Nelfinavir, triggers inflammasome formation and elicits an IL-1R–dependent inflammation in mice. We found that Nelfinavir impaired the maturation of lamin A, a structural component of the nuclear envelope, thereby promoting the release of DNA in the cytosol. Moreover, deficiency of the cytosolic DNA-sensor AIM2 impaired Nelfinavir-mediated inflammasome activation. These findings identify a pharmacologic activator of inflammasome and demonstrate the role of AIM2 in detecting endogenous DNA release upon perturbation of nuclear envelope integrity.
12
Ma, Jialu, Shasha Zhao, Xiao Gao, Rui Wang, Juan Liu, Xiangmei Zhou, and Yang Zhou. "The Roles of Inflammasomes in Host Defense against Mycobacterium tuberculosis." Pathogens 10, no. 2 (January 25, 2021): 120. http://dx.doi.org/10.3390/pathogens10020120.
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Mycobacterium tuberculosis (MTB) infection is characterized by granulomatous lung lesions and systemic inflammatory responses during active disease. Inflammasome activation is involved in regulation of inflammation. Inflammasomes are multiprotein complexes serving a platform for activation of caspase-1, which cleaves the proinflammatory cytokines such as interleukin-1β (IL-1β) and IL-18 into their active forms. These cytokines play an essential role in MTB control. MTB infection triggers activation of the nucleotide-binding domain, leucine-rich-repeat containing family, pyrin domain-containing 3 (NLRP3) and absent in melanoma 2 (AIM2) inflammasomes in vitro, but only AIM2 and apoptosis-associated speck-like protein containing a caspase-activation recruitment domain (ASC), rather than NLRP3 or caspase-1, favor host survival and restriction of mycobacterial replication in vivo. Interferons (IFNs) inhibits MTB-induced inflammasome activation and IL-1 signaling. In this review, we focus on activation and regulation of the NLRP3 and AIM2 inflammasomes after exposure to MTB, as well as the effect of inflammasome activation on host defense against the infection.
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Hayes, Cooper K., Douglas R. Wilcox, Yuchen Yang, Grace K. Coleman, Melissa A. Brown, and Richard Longnecker. "ASC-dependent inflammasomes contribute to immunopathology and mortality in herpes simplex encephalitis." PLOS Pathogens 17, no. 2 (February 1, 2021): e1009285. http://dx.doi.org/10.1371/journal.ppat.1009285.
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Herpes simplex virus encephalitis (HSE) is the most common cause of sporadic viral encephalitis, and despite targeted antiviral therapy, outcomes remain poor. Although the innate immune system is critical for restricting herpes simplex virus type I (HSV-1) in the brain, there is evidence that prolonged neuroinflammation contributes to HSE pathogenesis. In this study, we investigated the contribution of inflammasomes to disease pathogenesis in a murine model of HSE. Inflammasomes are signaling platforms that activate the pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18. We found that mice deficient in the inflammasome adaptor protein, apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC), had significantly improved survival and lower levels of IL-1β and IL-18 in the brain. Importantly, this difference in survival was independent of viral replication in the central nervous system (CNS). We found that microglia, the resident macrophages of the CNS, are the primary mediators of the ASC-dependent inflammasome response during infection. Using in vitro glial infections and a murine HSE model, we demonstrate that inflammasome activation contributes to the expression of chemokine (C-C motif) ligand 6 (CCL6), a leukocyte chemoattractant. The lower concentration of CCL6 in the brains of ASC-/- mice correlated with lower numbers of infiltrating macrophages during infection. Together, these data suggest that inflammasomes contribute to pathogenic inflammation in HSE and provide a mechanistic link between glial inflammasome activation and leukocyte infiltration. The contribution of inflammasomes to survival was independent of viral replication in our study, suggesting a promising new target in combating harmful inflammation in HSE.
14
Devi, Savita, Christian Stehlik, and Andrea Dorfleutner. "An Update on CARD Only Proteins (COPs) and PYD Only Proteins (POPs) as Inflammasome Regulators." International Journal of Molecular Sciences 21, no. 18 (September 20, 2020): 6901. http://dx.doi.org/10.3390/ijms21186901.
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Inflammasomes are protein scaffolds required for the activation of caspase-1 and the subsequent release of interleukin (IL)-1β, IL-18, and danger signals, as well as the induction of pyroptotic cell death to restore homeostasis following infection and sterile tissue damage. However, excessive inflammasome activation also causes detrimental inflammatory disease. Therefore, extensive control mechanisms are necessary to prevent improper inflammasome responses and inflammatory disease. Inflammasomes are assembled by sequential nucleated polymerization of Pyrin domain (PYD) and caspase recruitment domain (CARD)-containing inflammasome components. Once polymerization is nucleated, this process proceeds in a self-perpetuating manner and represents a point of no return. Therefore, regulation of this key step is crucial for a controlled inflammasome response. Here, we provide an update on two single domain protein families containing either a PYD or a CARD, the PYD-only proteins (POPs) and CARD-only proteins (COPs), respectively. Their structure allows them to occupy and block access to key protein–protein interaction domains necessary for inflammasome assembly, thereby regulating the threshold of these nucleated polymerization events, and consequently, the inflammatory host response.
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El-Sharkawy, Lina Y., David Brough, and Sally Freeman. "Inhibiting the NLRP3 Inflammasome." Molecules 25, no. 23 (November 25, 2020): 5533. http://dx.doi.org/10.3390/molecules25235533.
Full textAbstract:
Inflammasomes are protein complexes which are important in several inflammatory diseases. Inflammasomes form part of the innate immune system that triggers the activation of inflammatory cytokines interleukin (IL)-1β and IL-18. The inflammasome most studied in sterile inflammation and non-communicable disease is the NLRP3 inflammasome. Upon activation by diverse pathogen or disease associated signals, NLRP3 nucleates the oligomerization of an adaptor protein ASC forming a platform (the inflammasome) for the recruitment and activation of the protease caspase-1. Active caspase-1 catalyzes the processing and release of IL-1β and IL-18, and via cleavage of the pore forming protein gasdermin D can drive pyroptotic cell death. This review focuses on the structural basis and mechanism for NLRP3 inflammasome signaling in the context of drug design, providing chemical structures, activities, and clinical potential of direct inflammasome inhibitors. A cryo-EM structure of NLRP3 bound to NEK7 protein provides structural insight and aids in the discovery of novel NLRP3 inhibitors utilizing ligand-based or structure-based approaches.
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Angosto-Bazarra, Diego, Cristina Molina-López, Alejandro Peñín-Franch, Laura Hurtado-Navarro, and Pablo Pelegrín. "Techniques to Study Inflammasome Activation and Inhibition by Small Molecules." Molecules 26, no. 6 (March 18, 2021): 1704. http://dx.doi.org/10.3390/molecules26061704.
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Inflammasomes are immune cytosolic oligomers involved in the initiation and progression of multiple pathologies and diseases. The tight regulation of these immune sensors is necessary to control an optimal inflammatory response and recover organism homeostasis. Prolonged activation of inflammasomes result in the development of chronic inflammatory diseases, and the use of small drug-like inhibitory molecules are emerging as promising anti-inflammatory therapies. Different aspects have to be taken in consideration when designing inflammasome inhibitors. This review summarizes the different techniques that can be used to study the mechanism of action of potential inflammasome inhibitory molecules.
17
Missiroli, Sonia, Mariasole Perrone, Caterina Boncompagni, Chiara Borghi, Alberto Campagnaro, Francesco Marchetti, Gabriele Anania, et al. "Targeting the NLRP3 Inflammasome as a New Therapeutic Option for Overcoming Cancer." Cancers 13, no. 10 (May 11, 2021): 2297. http://dx.doi.org/10.3390/cancers13102297.
Full textAbstract:
Inflammasomes are multiprotein complexes that regulate the maturation and secretion of the proinflammatory cytokines interleukin-1beta (IL-1β and interleukin-18 (IL-18) in response to various intracellular stimuli. As a member of the inflammasomes family, NLRP3 is the most studied and best characterized inflammasome and has been shown to be involved in several pathologies. Recent findings have made it increasingly apparent that the NLRP3 inflammasome may also play a central role in tumorigenesis, and it has attracted attention as a potential anticancer therapy target. In this review, we discuss the role of NLRP3 in the development and progression of cancer, offering a detailed summary of NLRP3 inflammasome activation (and inhibition) in the pathogenesis of various forms of cancer. Moreover, we focus on the therapeutic potential of targeting NLRP3 for cancer therapy, emphasizing how understanding NLRP3 inflammasome-dependent cancer mechanisms might guide the development of new drugs that target the inflammatory response of tumor-associated cells.
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Chi, Kun, Xiaodong Geng, Chao Liu, GuangYan Cai, and Quan Hong. "Research Progress on the Role of Inflammasomes in Kidney Disease." Mediators of Inflammation 2020 (January 29, 2020): 1–9. http://dx.doi.org/10.1155/2020/8032797.
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Inflammasomes are multimeric complexes composed of cytoplasmic sensors, apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC or PYCARD), and procaspase-1 and play roles in regulating caspase-dependent inflammation and cell death. Inflammasomes are assembled by sensing pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) and initiate inflammatory responses by activating caspase-1. Activated caspase-1 promotes the release of the inflammatory cytokines interleukin-1β (IL-1β) and IL-18 and eventually induces pyroptosis. Inflammasomes are closely related to kidney diseases. In particular, the NLRP3 (NACHT, LRR, and PYD domain-containing protein 3) inflammasome has been shown to cause acute and chronic kidney diseases by regulating canonical and noncanonical mechanisms of inflammation. Small-molecule inhibitors that target NLRP3 and other components of the inflammasome are potential options for the treatment of kidney-related diseases such as diabetic nephropathy. This article will focus on the research progress on inflammasomes and the key pathogenic roles of inflammasomes in the development and progression of kidney diseases and explore the potential of this intracellular inflammation to further prevent or block the development of the kidney disease.
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Ivanov, Konstantin, Ekaterina Garanina, Albert Rizvanov, and Svetlana Khaiboullina. "Inflammasomes as Targets for Adjuvants." Pathogens 9, no. 4 (March 30, 2020): 252. http://dx.doi.org/10.3390/pathogens9040252.
Full textAbstract:
Inflammasomes are an essential part of the innate immune system. They are necessary for the development of a healthy immune response against infectious diseases. Inflammasome activation leads to the secretion of pro-inflammatory cytokines such as IL-1β and IL-18, which stimulate the adaptive immune system. Inflammasomes activators can be used as adjuvants to provide and maintain the strength of the immune response. This review is focused on the mechanisms of action and the effects of adjuvants on inflammasomes. The therapeutic and prophylaxis significance of inflammasomes in infectious diseases is also discussed.
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Burton, Eric M., Raphaela Goldbach-Mansky, and Sumita Bhaduri-McIntosh. "A promiscuous inflammasome sparks replication of a common tumor virus." Proceedings of the National Academy of Sciences 117, no. 3 (January 9, 2020): 1722–30. http://dx.doi.org/10.1073/pnas.1919133117.
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Viruses activate inflammasomes but then subvert resulting inflammatory responses to avoid elimination. We asked whether viruses could instead use such activated or primed inflammasomes to directly aid their propagation and spread. Since herpesviruses are experts at coopting cellular functions, we investigated whether Epstein−Barr virus (EBV), an oncoherpesvirus, exploits inflammasomes to activate its replicative or lytic phase. Indeed, our experiments reveal that EBV exploits several inflammasome sensors to actually activate its replicative phase from quiescence/latency. In particular, TXNIP, a key inflammasome intermediary, causes assembly of the NLRP3 inflammasome, resulting in caspase-1−mediated depletion of the heterochromatin-inducing epigenetic repressor KAP1/TRIM28 in a subpopulation of cells. As a result, only TXNIPhiKAP1lo cells, that is, in a primed/prolytic state, turn expression of the replication/lytic/reactivation switch protein on to enter the replicative phase. Our findings 1) demonstrate that EBV dovetails its escape strategy to a key cellular danger-sensing mechanism, 2) indicate that transcription may be regulated by KAP1 abundance aside from canonical regulation through its posttranslational modification, 3) mechanistically link diabetes, which frequently activates the NLRP3 inflammasome, to deregulation of a tumor virus, and 4) demonstrate that B lymphocytes from NOMID (neonatal onset multisystem inflammatory disease) patients who have NLRP3 mutations and suffer from hyperactive innate responses are defective in controlling a herpesvirus.
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Poli, Giulia, Consuelo Fabi, Marina Maria Bellet, Claudio Costantini, Luisa Nunziangeli, Luigina Romani, and Stefano Brancorsini. "Epigenetic Mechanisms of Inflammasome Regulation." International Journal of Molecular Sciences 21, no. 16 (August 11, 2020): 5758. http://dx.doi.org/10.3390/ijms21165758.
Full textAbstract:
The innate immune system represents the host’s first-line defense against pathogens, dead cells or environmental factors. One of the most important inflammatory pathways is represented by the activation of the NOD-like receptor (NLR) protein family. Some NLRs induce the assembly of large caspase-1-activating complexes called inflammasomes. Different types of inflammasomes have been identified that can respond to distinct bacterial, viral or fungal infections; sterile cell damage or other stressors, such as metabolic imbalances. Epigenetic regulation has been recently suggested to provide a complementary mechanism to control inflammasome activity. This regulation can be exerted through at least three main mechanisms, including CpG DNA methylation, histones post-translational modifications and noncoding RNA expression. The repression or promotion of expression of different inflammasomes (NLRP1, NLRP2, NLRP3, NLRP4, NLRP6, NLRP7, NLRP12 and AIM2) through epigenetic mechanisms determines the development of pathologies with variable severity. For example, our team recently explored the role of microRNAs (miRNAs) targeting and modulating the components of the inflammasome as potential biomarkers in bladder cancer and during therapy. This suggests that the epigenetic control of inflammasome-related genes could represent a potential target for further investigations of molecular mechanisms regulating inflammatory pathways.
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Yang, Lijing, Mengjia Hu, Yukai Lu, Songling Han, and Junping Wang. "Inflammasomes and the Maintenance of Hematopoietic Homeostasis: New Perspectives and Opportunities." Molecules 26, no. 2 (January 9, 2021): 309. http://dx.doi.org/10.3390/molecules26020309.
Full textAbstract:
Hematopoietic stem cells (HSCs) regularly produce various blood cells throughout life via their self-renewal, proliferation, and differentiation abilities. Most HSCs remain quiescent in the bone marrow (BM) and respond in a timely manner to either physiological or pathological cues, but the underlying mechanisms remain to be further elucidated. In the past few years, accumulating evidence has highlighted an intermediate role of inflammasome activation in hematopoietic maintenance, post-hematopoietic transplantation complications, and senescence. As a cytosolic protein complex, the inflammasome participates in immune responses by generating a caspase cascade and inducing cytokine secretion. This process is generally triggered by signals from purinergic receptors that integrate extracellular stimuli such as the metabolic factor ATP via P2 receptors. Furthermore, targeted modulation/inhibition of specific inflammasomes may help to maintain/restore adequate hematopoietic homeostasis. In this review, we will first summarize the possible relationships between inflammasome activation and homeostasis based on certain interesting phenomena. The cellular and molecular mechanism by which purinergic receptors integrate extracellular cues to activate inflammasomes inside HSCs will then be described. We will also discuss the therapeutic potential of targeting inflammasomes and their components in some diseases through pharmacological or genetic strategies.
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Yang, Lijing, Mengjia Hu, Yukai Lu, Songling Han, and Junping Wang. "Inflammasomes and the Maintenance of Hematopoietic Homeostasis: New Perspectives and Opportunities." Molecules 26, no. 2 (January 9, 2021): 309. http://dx.doi.org/10.3390/molecules26020309.
Full textAbstract:
Hematopoietic stem cells (HSCs) regularly produce various blood cells throughout life via their self-renewal, proliferation, and differentiation abilities. Most HSCs remain quiescent in the bone marrow (BM) and respond in a timely manner to either physiological or pathological cues, but the underlying mechanisms remain to be further elucidated. In the past few years, accumulating evidence has highlighted an intermediate role of inflammasome activation in hematopoietic maintenance, post-hematopoietic transplantation complications, and senescence. As a cytosolic protein complex, the inflammasome participates in immune responses by generating a caspase cascade and inducing cytokine secretion. This process is generally triggered by signals from purinergic receptors that integrate extracellular stimuli such as the metabolic factor ATP via P2 receptors. Furthermore, targeted modulation/inhibition of specific inflammasomes may help to maintain/restore adequate hematopoietic homeostasis. In this review, we will first summarize the possible relationships between inflammasome activation and homeostasis based on certain interesting phenomena. The cellular and molecular mechanism by which purinergic receptors integrate extracellular cues to activate inflammasomes inside HSCs will then be described. We will also discuss the therapeutic potential of targeting inflammasomes and their components in some diseases through pharmacological or genetic strategies.
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Finethy, Ryan, Ine Jorgensen, Arun K. Haldar, Marcel R. de Zoete, Till Strowig, Richard A. Flavell, Masahiro Yamamoto, Uma M. Nagarajan, Edward A. Miao, and Jörn Coers. "Guanylate Binding Proteins Enable Rapid Activation of Canonical and Noncanonical Inflammasomes in Chlamydia-Infected Macrophages." Infection and Immunity 83, no. 12 (September 28, 2015): 4740–49. http://dx.doi.org/10.1128/iai.00856-15.
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Interferon (IFN)-inducible guanylate binding proteins (GBPs) mediate cell-autonomous host resistance to bacterial pathogens and promote inflammasome activation. The prevailing model postulates that these two GBP-controlled activities are directly linked through GBP-dependent vacuolar lysis. It was proposed that the rupture of pathogen-containing vacuoles (PVs) by GBPs destroyed the microbial refuge and simultaneously contaminated the host cell cytosol with microbial activators of inflammasomes. Here, we demonstrate that GBP-mediated host resistance and GBP-mediated inflammatory responses can be uncoupled. We show that PVs formed by the rodent pathogenChlamydia muridarum, so-called inclusions, remain free of GBPs and thatC. muridarumis impervious to GBP-mediated restrictions on bacterial growth. Although GBPs neither bind toC. muridaruminclusions nor restrictC. muridarumgrowth, we find that GBPs promote inflammasome activation inC. muridarum-infected macrophages. We demonstrate thatC. muridaruminfections induce GBP-dependent pyroptosis through both caspase-11-dependent noncanonical and caspase-1-dependent canonical inflammasomes. Among canonical inflammasomes, we find thatC. muridarumand the human pathogenChlamydia trachomatisactivate not only NLRP3 but also AIM2. Our data show that GBPs support fast-kinetics processing and secretion of interleukin-1β (IL-1β) and IL-18 by the NLRP3 inflammasome but are dispensable for the secretion of the same cytokines at later times postinfection. Because IFN-γ fails to induce IL-1β transcription, GBP-dependent fast-kinetics inflammasome activation can drive the preferential processing of constitutively expressed IL-18 in IFN-γ-primed macrophages in the absence of prior Toll-like receptor stimulation. Together, our results reveal that GBPs control the kinetics of inflammasome activation and thereby shape macrophage responses toChlamydiainfections.
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Gram, Anna M., Joost Frenkel, and Maaike E. Ressing. "Inflammasomes and viruses: cellular defence versus viral offence." Journal of General Virology 93, no. 10 (October 1, 2012): 2063–75. http://dx.doi.org/10.1099/vir.0.042978-0.
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Pro-inflammatory cytokines are important mediators in immune responses against invading pathogens, including viruses. Precursors of the pro-inflammatory cytokines interleukin (IL)-1β and IL-18 are processed by caspase-1. Caspase-1 is activated through autocleavage, but how this is regulated remained elusive for a long time. In 2002, an intracellular multimeric complex was discovered that facilitated caspase-1 cleavage and was termed ‘inflammasome’. To date, different inflammasomes have been described, which recognize a variety of ligands and pathogens. In this review, we discuss the role of inflammasomes in sensing viral infection as well as the evasion strategies that viruses developed to circumvent inflammasome-dependent effects.
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Boucher, Dave, Mercedes Monteleone, Rebecca C. Coll, Kaiwen W. Chen, Connie M. Ross, Jessica L. Teo, Guillermo A. Gomez, et al. "Caspase-1 self-cleavage is an intrinsic mechanism to terminate inflammasome activity." Journal of Experimental Medicine 215, no. 3 (February 6, 2018): 827–40. http://dx.doi.org/10.1084/jem.20172222.
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Host-protective caspase-1 activity must be tightly regulated to prevent pathology, but mechanisms controlling the duration of cellular caspase-1 activity are unknown. Caspase-1 is activated on inflammasomes, signaling platforms that facilitate caspase-1 dimerization and autoprocessing. Previous studies with recombinant protein identified a caspase-1 tetramer composed of two p20 and two p10 subunits (p20/p10) as an active species. In this study, we report that in the cell, the dominant species of active caspase-1 dimers elicited by inflammasomes are in fact full-length p46 and a transient species, p33/p10. Further p33/p10 autoprocessing occurs with kinetics specified by inflammasome size and cell type, and this releases p20/p10 from the inflammasome, whereupon the tetramer becomes unstable in cells and protease activity is terminated. The inflammasome–caspase-1 complex thus functions as a holoenzyme that directs the location of caspase-1 activity but also incorporates an intrinsic self-limiting mechanism that ensures timely caspase-1 deactivation. This intrinsic mechanism of inflammasome signal shutdown offers a molecular basis for the transient nature, and coordinated timing, of inflammasome-dependent inflammatory responses.
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Casson, Cierra N., Janet Yu, Valeria M. Reyes, Frances O. Taschuk, Anjana Yadav, Alan M. Copenhaver, Hieu T. Nguyen, Ronald G. Collman, and Sunny Shin. "Human caspase-4 mediates noncanonical inflammasome activation against gram-negative bacterial pathogens." Proceedings of the National Academy of Sciences 112, no. 21 (May 11, 2015): 6688–93. http://dx.doi.org/10.1073/pnas.1421699112.
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Inflammasomes are critical for host defense against bacterial pathogens. In murine macrophages infected by gram-negative bacteria, the canonical inflammasome activates caspase-1 to mediate pyroptotic cell death and release of IL-1 family cytokines. Additionally, a noncanonical inflammasome controlled by caspase-11 induces cell death and IL-1 release. However, humans do not encode caspase-11. Instead, humans encode two putative orthologs: caspase-4 and caspase-5. Whether either ortholog functions similar to caspase-11 is poorly defined. Therefore, we sought to define the inflammatory caspases in primary human macrophages that regulate inflammasome responses to gram-negative bacteria. We find that human macrophages activate inflammasomes specifically in response to diverse gram-negative bacterial pathogens that introduce bacterial products into the host cytosol using specialized secretion systems. In primary human macrophages, IL-1β secretion requires the caspase-1 inflammasome, whereas IL-1α release and cell death are caspase-1–independent. Instead, caspase-4 mediates IL-1α release and cell death. Our findings implicate human caspase-4 as a critical regulator of noncanonical inflammasome activation that initiates defense against bacterial pathogens in primary human macrophages.
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Magupalli, Venkat Giri, Roberto Negro, Yuzi Tian, Arthur V. Hauenstein, Giuseppe Di Caprio, Wesley Skillern, Qiufang Deng, et al. "HDAC6 mediates an aggresome-like mechanism for NLRP3 and pyrin inflammasome activation." Science 369, no. 6510 (September 17, 2020): eaas8995. http://dx.doi.org/10.1126/science.aas8995.
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Inflammasomes are supramolecular complexes that play key roles in immune surveillance. This is accomplished by the activation of inflammatory caspases, which leads to the proteolytic maturation of interleukin 1β (IL-1β) and pyroptosis. Here, we show that nucleotide-binding domain, leucine-rich repeat, and pyrin domain–containing protein 3 (NLRP3)- and pyrin-mediated inflammasome assembly, caspase activation, and IL-1β conversion occur at the microtubule-organizing center (MTOC). Furthermore, the dynein adapter histone deacetylase 6 (HDAC6) is indispensable for the microtubule transport and assembly of these inflammasomes both in vitro and in mice. Because HDAC6 can transport ubiquitinated pathological aggregates to the MTOC for aggresome formation and autophagosomal degradation, its role in NLRP3 and pyrin inflammasome activation also provides an inherent mechanism for the down-regulation of these inflammasomes by autophagy. This work suggests an unexpected parallel between the formation of physiological and pathological aggregates.
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Li, Meihe, Tao Sun, Xiaoling Wu, Peng An, Xili Wu, and Huimin Dang. "Autophagy in the HTR-8/SVneo Cell Oxidative Stress Model Is Associated with the NLRP1 Inflammasome." Oxidative Medicine and Cellular Longevity 2021 (March 27, 2021): 1–15. http://dx.doi.org/10.1155/2021/2353504.
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We investigated whether there was activation of NLRP1 inflammasomes and excessive autophagy in oxidative stress damage. And we further demonstrate whether there is a cascade relationship between the activation of NLRP1 inflammasomes and the phenomenon of excessive autophagy. To observe the expression level of the NLRP1 inflammasome group in the pathological process of trophoblast cell oxidative stress, western blot, immunofluorescence, and qRT-PCR were performed. Autophagy in trophoblast cells after the action of H2O2 was detected by using normal trophoblast cells’ NLRP1-specific activator (MDP) as a positive control. The presence of excessive autophagy was determined by comparing it with the autophagy-related proteins in normal trophoblast cells. Through siRNA-NLRP1, we investigated the role of oxidative stress and the NLRP1 inflammasome in autophagy in cells. 100 μmol MDP for 24 hours can be used as the optimal concentration of the NLRP1 activator. In human placental trophoblast oxidative stress, the model group significantly increased the expression level of inflammasome IL-1β, CASP1, and NLRP1, compared with the control group NLRP3, and LC3-II, Beclin-1, ATG5, ATG7, and p62 overactivated the autophagy ability of cells. After the activation of NLRP1, the expression of these inflammasomes increased, accompanied by the decrease in autophagy. After the expression of NLRP1 was silenced by RNAi, the expression of inflammasome IL-1β, CASP1, and NLRP3 was also decreased. Still, the autophagy level was increased, which was manifested by the high expression of LC3-II, Beclin-1, ATG5, and ATG7 and the decrease in p62. Trophoblast cells showed the expression of NLRP1 protein and excessive autophagy under oxidative stress. Simultaneously, the NLRP1 inflammasome of trophoblast cells in the state of oxidative stress was correlated with autophagy. Inflammasome activation and autophagy were shown to be linked and to influence each other mutually. These may also provide new therapeutic targets in a pathological pregnancy.
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Xu, Qiuyun, Xiaorong Zhou, Warren Strober, and Liming Mao. "Inflammasome Regulation: Therapeutic Potential for Inflammatory Bowel Disease." Molecules 26, no. 6 (March 19, 2021): 1725. http://dx.doi.org/10.3390/molecules26061725.
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Inflammasomes are multiprotein complexes formed to regulate the maturation of pro-inflammatory caspases, in response to intracellular or extracellular stimulants. Accumulating studies showed that the inflammasomes are implicated in the pathogenesis of inflammatory bowel disease (IBD), although their activation is not a decisive factor for the development of IBD. Inflammasomes and related cytokines play an important role in the maintenance of gut immune homeostasis, while its overactivation might induce excess immune responses and consequently cause tissue damage in the gut. Emerging studies provide evidence that some genetic abnormalities might induce enhanced NLRP3 inflammasome activation and cause colitis. In these cases, the colonic inflammation can be ameliorated by blocking NLRP3 activation or its downstream cytokine IL-1β. A number of natural products were shown to play a role in preventing colon inflammation in various experimental colitis models. On the other hand, lack of inflammasome function also causes intestinal abnormalities. Thus, an appropriate regulation of inflammasomes might be a promising therapeutic strategy for IBD intervention. This review aims at summarizing the main findings in these studies and provide an outline for further studies that might contribute to our understanding of the role of inflammasomes in the pathogenesis and therapeutic treatment of IBD.
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Krakauer, Teresa. "Inflammasomes, Autophagy, and Cell Death: The Trinity of Innate Host Defense against Intracellular Bacteria." Mediators of Inflammation 2019 (January 8, 2019): 1–10. http://dx.doi.org/10.1155/2019/2471215.
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Inflammasome activation is an innate host defense mechanism initiated upon sensing pathogens or danger in the cytosol. Both autophagy and cell death are cell autonomous processes important in development, as well as in host defense against intracellular bacteria. Inflammasome, autophagy, and cell death pathways can be activated by pathogens, pathogen-associated molecular patterns (PAMPs), cell stress, and host-derived damage-associated molecular patterns (DAMPs). Phagocytosis and toll-like receptor (TLR) signaling induce reactive oxygen species (ROS), type I IFN, NFκB activation of proinflammatory cytokines, and the mitogen-activated protein kinase cascade. ROS and IFNγare also prominent inducers of autophagy. Pathogens, PAMPs, and DAMPs activate TLRs and intracellular inflammasomes, inducing apoptotic and inflammatory caspases in a context-dependent manner to promote various forms of cell death to eliminate pathogens. Common downstream signaling molecules of inflammasomes, autophagy, and cell death pathways interact to initiate appropriate measures against pathogens and determine host survival as well as pathological consequences of infection. The integration of inflammasome activation, autophagy, and cell death is central to pathogen clearance. Various pathogens produce virulence factors to control inflammasomes, subvert autophagy, and modulate host cell death in order to evade host defense. This review highlights the interaction of inflammasomes, autophagy, and host cell death pathways in counteractingBurkholderia pseudomallei, the causative agent of melioidosis. Contrasting evasion strategies used byB.pseudomallei,Mycobacterium tuberculosis, andLegionella pneumophilato avoid and dampen these innate immune responses will be discussed.
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Masood, Humaira, Ruochen Che, and Aihua Zhang. "Inflammasomes in the Pathophysiology of Kidney Diseases." Kidney Diseases 1, no. 3 (2015): 187–93. http://dx.doi.org/10.1159/000438843.
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Background: The inflammasome is a complex of proteins in the cytoplasm that consists of three main components: a sensor protein (receptor), an adapter protein and caspase-1. Inflammasomes are the critical components of innate immunity and have been gradually recognized as a critical mediator in various autoimmune diseases; also, their role in chronic kidney disease and acute kidney injury has been gradually accepted. Summary: Inflammasomes triggered by infectious or sterile injuries transfer proinflammatory mediators into mature ones through innate danger-signaling platforms. Information on inflammasomes in kidney disease will help to uncover the underlying mechanisms of nephropathy and provide novel therapeutic targets in the future. Key Messages: The inflammasomes can be activated by a series of exogenous and endogenous stimuli, including pathogen-and danger-associated molecular patterns released from or caused by damaged cells. The NACHT, LRR and PYD domain-containing protein 3 (NLRP3) in the kidney exerts its effect not only by the ‘canonical' pathway of IL-1β and IL-18 secretion but also by ‘noncanonical' pathways, such as tumor growth factor-β signaling, epithelial-mesenchymal transition and fibrosis. In both clinical and experimental data, the NLRP3 inflammasome was reported to be involved in the pathogenesis of chronic kidney disease and acute kidney injury. However, the underlying mechanisms are not fully understood. Therapies targeting the activation of the NLRP3 inflammasome or blocking its downstream effectors appear attractive for the pursuit of neuropathy treatments.
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Feria-Garzón, Manuel G., María T. Rugeles, Juan C. Hernandez, Jorge A. Lujan, and Natalia A. Taborda. "Sulfasalazine as an Immunomodulator of the Inflammatory Process during HIV-1 Infection." International Journal of Molecular Sciences 20, no. 18 (September 11, 2019): 4476. http://dx.doi.org/10.3390/ijms20184476.
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Background: HIV-1 induces an uncontrolled inflammatory response of several immune components, such as inflammasomes. These molecular complexes, associated with Toll-like receptor (TLR) activity, induce the maturation and release of IL-1β and IL-18 and eventually induce pyroptosis. It has been previously demonstrated that HIV induces inflammasome activation, which is significantly lower in the gastrointestinal tissue and blood from people living with HIV-1 with spontaneous control of viral replication. Therefore, immunomodulatory agents could be useful in improving HIV prognosis. Objective: To evaluate the potential inhibitory effect of sulfasalazine (SSZ) on inflammasomes and TLRs in peripheral blood mononuclear cells (PBMCs) from people living with HIV and healthy donors. Methods: PBMCs were obtained from 15 people living with HIV and 15 healthy donors. Cells were stimulated with agonists of TLRs and inflammasomes and subsequently treated with SSZ. The concentration of IL-1β and the relative expression of NLRP3, NLRC4, NLRP1, AIM2, ASC, Caspase-1, IL-1β, and IL-18 were quantified. Results: Cells treated with SSZ exhibited a decreased IL-1β production after inflammasome and TLR stimulation, as well as regulation of inflammasome-related genes, in both people with HIV and healthy individuals. The concentration of IL-1β was positively correlated with the CD4+ T-cell count and negatively with the viral load. Conclusion: Our results suggest that SSZ has an immunomodulatory effect on inflammasome and TLR activation that depends on the clinical HIV status.
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Tabeeva, G. I., M. R. Dumanovskaya, A. V. Asaturova, I. M. Bogdanova, S. Z. Sanaya, and A. V. Tregubova. "Features of regulation and function of inflammasomes in inflammatory diseases of the female reproductive system." CLINICAL AND EXPERIMENTAL MORPHOLOGY 9, no. 3 (September 23, 2020): 12–20. http://dx.doi.org/10.31088/cem2020.9.3.12-20.
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Chronic inflammation underlies the progression of many human systemic disorders, including a number of gynecological diseases such as endometriosis and chronic endometritis. Inflammasomes play a special role in the regulation of intercellular interactions under physiological and pathological conditions. The pathogenesis of chronic inflammation assumes a gradual course, accompanied by prolonged maintenance active state of inflammasomes due to the excessive accumulation of intracellular and extracellular endogenous molecules released from destroyed cells – DAMPs (damage-associated molecular patterns), their ineffective utilization by autophagy and stress-reducing cell systems, local production of pro-inflammatory cytokines (IL-1β, IL-18), as well as ROS (reactive oxygen species), accumulation of macrophages and T-lymphocytes, tissue damage and the development of fibrosis. The proteins of the inflammasome complex can serve as targets for drugs, which will increase the efficiency of therapy for inflammation-associated diseases. This review presents the current data on the role of NLRP3-inflammasomes in immune regulation and the molecular mechanisms underlying the pathogenesis of endometriosis and chronic endometritis. Understanding the molecular mechanisms of inflammasome activation and the discovery of their effective inhibitors, as well as the assessment of the therapeutic potential in these pathologies, is an important direction of future research. Keywords: inflammasome, inflammation, innate immunity, endometriosis, chronic endometritis
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Witola, William H., Ernest Mui, Aubrey Hargrave, Susan Liu, Magali Hypolite, Alexandre Montpetit, Pierre Cavailles, et al. "NALP1 Influences Susceptibility to Human Congenital Toxoplasmosis, Proinflammatory Cytokine Response, and Fate ofToxoplasma gondii-Infected Monocytic Cells." Infection and Immunity 79, no. 2 (November 22, 2010): 756–66. http://dx.doi.org/10.1128/iai.00898-10.
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ABSTRACTNALP1 is a member of the NOD-like receptor (NLR) family of proteins that form inflammasomes. Upon cellular infection or stress, inflammasomes are activated, triggering maturation of proinflammatory cytokines and downstream cellular signaling mediated through the MyD88 adaptor.Toxoplasma gondiiis an obligate intracellular parasite that stimulates production of high levels of proinflammatory cytokines that are important in innate immunity. In this study, susceptibility alleles for human congenital toxoplasmosis were identified in the NALP1 gene. To investigate the role of the NALP1 inflammasome during infection withT. gondii, we genetically engineered a human monocytic cell line for NALP1 gene knockdown by RNA interference. NALP1 silencing attenuated progression ofT. gondiiinfection, with accelerated host cell death and eventual cell disintegration. In line with this observation, upregulation of the proinflammatory cytokines interleukin-1β (IL-1β), IL-18, and IL-12 uponT. gondiiinfection was not observed in monocytic cells with NALP1 knockdown. These findings suggest that the NALP1 inflammasome is critical for mediating innate immune responses toT. gondiiinfection and pathogenesis. Although there have been recent advances in understanding the potent activity of inflammasomes in directing innate immune responses to disease, this is the first report, to our knowledge, on the crucial role of the NALP1 inflammasome in the pathogenesis ofT. gondiiinfections in humans.
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Gora, Ilona M., Anna Ciechanowska, and Piotr Ladyzynski. "NLRP3 Inflammasome at the Interface of Inflammation, Endothelial Dysfunction, and Type 2 Diabetes." Cells 10, no. 2 (February 3, 2021): 314. http://dx.doi.org/10.3390/cells10020314.
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Type 2 diabetes mellitus (T2DM), accounting for 90–95% cases of diabetes, is characterized by chronic inflammation. The mechanisms that control inflammation activation in T2DM are largely unexplored. Inflammasomes represent significant sensors mediating innate immune responses. The aim of this work is to present a review of links between the NLRP3 inflammasome, endothelial dysfunction, and T2DM. The NLRP3 inflammasome activates caspase-1, which leads to the maturation of pro-inflammatory cytokines interleukin 1β and interleukin 18. In this review, we characterize the structure and functions of NLRP3 inflammasome as well as the most important mechanisms and molecules engaged in its activation. We present evidence of the importance of the endothelial dysfunction as the first key step to activating the inflammasome, which suggests that suppressing the NLRP3 inflammasome could be a new approach in depletion hyperglycemic toxicity and in averting the onset of vascular complications in T2DM. We also demonstrate reports showing that the expression of a few microRNAs that are also known to be involved in either NLRP3 inflammasome activation or endothelial dysfunction is deregulated in T2DM. Collectively, this evidence suggests that T2DM is an inflammatory disease stimulated by pro-inflammatory cytokines. Finally, studies revealing the role of glucose concentration in the activation of NLRP3 inflammasome are analyzed. The more that is known about inflammasomes, the higher the chances to create new, effective therapies for patients suffering from inflammatory diseases. This may offer potential novel therapeutic perspectives in T2DM prevention and treatment.
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Ciążyńska, Magdalena, Irmina Olejniczak-Staruch, Dorota Sobolewska-Sztychny, Joanna Narbutt, Małgorzata Skibińska, and Aleksandra Lesiak. "The Role of NLRP1, NLRP3, and AIM2 Inflammasomes in Psoriasis: Review." International Journal of Molecular Sciences 22, no. 11 (May 31, 2021): 5898. http://dx.doi.org/10.3390/ijms22115898.
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Inflammasomes are high-molecular-weight protein complexes that may cleave the two main proinflammatory cytokines, pro-interleukin-1β and pro-interleukin-18, into active forms, and contribute to psoriasis. Despite recent advances made in the pathogenesis of psoriasis, mainly studied as an autoimmune condition, activation of immune response triggers of psoriasis is still not completely understood. Recently, focus was placed on the role of inflammasomes in the pathogenesis of psoriasis. Multiple types of inhibitors and activators of various inflammasomes, inflammasome-related genes, and genetic susceptibility loci were recognized in psoriasis. In this systemic review, we collect recent and comprehensive evidence from the inflammasomes, NLRP1, NLRP3, and AIM2, in pathogenesis of psoriasis.
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Hoque, Rafaz, and Wajahat Z. Mehal. "Inflammasomes in pancreatic physiology and disease." American Journal of Physiology-Gastrointestinal and Liver Physiology 308, no. 8 (April 15, 2015): G643—G651. http://dx.doi.org/10.1152/ajpgi.00388.2014.
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In this review we summarize the role of inflammasomes in pancreatic physiology and disease with a focus on acute pancreatitis where much recent progress has been made. New findings have identified inducers of and cell specificity of inflammasome component expression in the pancreas, the contribution of inflammasome-regulated effectors to pancreatitis, and metabolic regulation of inflammasome activation, which are strong determinants of injury in pancreatitis. New areas of pancreatic biology will be highlighted in the context of our evolving understanding of gut microbiome- and injury-induced inflammasome priming, pyroptosis, and innate immune-mediated regulation of cell metabolism.
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Lamkanfi, Mohamed, James L. Mueller, Alberto C. Vitari, Shahram Misaghi, Anna Fedorova, Kurt Deshayes, Wyne P. Lee, Hal M. Hoffman, and Vishva M. Dixit. "Glyburide inhibits the Cryopyrin/Nalp3 inflammasome." Journal of Cell Biology 187, no. 1 (October 5, 2009): 61–70. http://dx.doi.org/10.1083/jcb.200903124.
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Inflammasomes activate caspase-1 for processing and secretion of the cytokines interleukin-1β (IL-1β) and IL-18. Cryopyrin/NALP3/NLRP3 is an essential component of inflammasomes triggered by microbial ligands, danger-associated molecular patterns (DAMPs), and crystals. Inappropriate Cryopyrin activity has been incriminated in the pathogenesis of gouty arthritis, Alzheimer's, and silicosis. Therefore, inhibitors of the Nalp3 inflammasome offer considerable therapeutic promise. In this study, we show that the type 2 diabetes drug glyburide prevented activation of the Cryopyrin inflammasome. Glyburide's cyclohexylurea group, which binds to adenosine triphosphatase (ATP)–sensitive K+ (KATP) channels for insulin secretion, is dispensable for inflammasome inhibition. Macrophages lacking KATP subunits or ATP-binding cassette transporters also activate the Cryopyrin inflammasome normally. Glyburide analogues inhibit ATP- but not hypothermia-induced IL-1β secretion from human monocytes expressing familial cold-associated autoinflammatory syndrome–associated Cryopyrin mutations, thus suggesting that inhibition occurs upstream of Cryopyrin. Concurrent with the role of Cryopyrin in endotoxemia, glyburide significantly delays lipopolysaccharide-induced lethality in mice. Therefore, glyburide is the first identified compound to prevent Cryopyrin activation and microbial ligand-, DAMP-, and crystal-induced IL-1β secretion.
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Hatscher, Lukas, Christian H. K. Lehmann, Ariawan Purbojo, Constantin Onderka, Chunguang Liang, Arndt Hartmann, Robert Cesnjevar, et al. "Select hyperactivating NLRP3 ligands enhance the TH1- and TH17-inducing potential of human type 2 conventional dendritic cells." Science Signaling 14, no. 680 (April 27, 2021): eabe1757. http://dx.doi.org/10.1126/scisignal.abe1757.
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The detection of microorganisms and danger signals by pattern recognition receptors on dendritic cells (DCs) and the consequent formation of inflammasomes are pivotal for initiating protective immune responses. Although the activation of inflammasomes leading to secretion of the cytokine IL-1β is typically accompanied by pyroptosis (an inflammatory form of lytic programmed cell death), some cells can survive and exist in a state of hyperactivation. Here, we found that the conventional type 2 DC (cDC2) subset is the major human DC subset that is transcriptionally and functionally poised for inflammasome formation and response without pyroptosis. When cDC2 were stimulated with ligands that relatively weakly activated the inflammasome, the cells did not enter pyroptosis but instead secreted IL-12 family cytokines and IL-1β. These cytokines induced prominent T helper type 1 (TH1) and TH17 responses that were superior to those seen in response to Toll-like receptor (TLR) stimulation alone or to stronger, classical inflammasome ligands. These findings not only define the human cDC2 subpopulation as a prime target for the treatment of inflammasome-dependent inflammatory diseases but may also inform new approaches for adjuvant and vaccine development.
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Han, Chuanhui, Victoria Godfrey, Zhida Liu, Yanfei Han, Longchao Liu, Hua Peng, Ralph R. Weichselbaum, Hasan Zaki, and Yang-Xin Fu. "The AIM2 and NLRP3 inflammasomes trigger IL-1–mediated antitumor effects during radiation." Science Immunology 6, no. 59 (May 7, 2021): eabc6998. http://dx.doi.org/10.1126/sciimmunol.abc6998.
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The inflammasome promotes inflammation-associated diseases, including cancer, and contributes to the radiation-induced tissue damage. However, the role of inflammasome in radiation-induced antitumor effects is unclear. We observed that tumors transplanted in Casp1−/− mice were resistant to radiation treatment compared with tumors in wild-type (WT) mice. To map out which molecule in the inflammasome pathway contributed to this resistant, we investigated the antitumor effect of radiation in several inflammasome-deficient mice. Tumors grown in either Aim2−/− or Nlrp3−/− mice remained sensitive to radiation, like WT mice, whereas Aim2−/−Nlrp3−/− mice showed radioresistance. Mechanistically, extracellular vesicles (EVs) and EV-free supernatant derived from irradiated tumors activated both Aim2 and Nlrp3 inflammasomes in macrophages, leading to the production of interleukin-1β (IL-1β). IL-1β treatment helped overcome the radioresistance of tumors growing in Casp1−/− and Aim2−/−Nlrp3−/− mice. IL-1 signaling in dendritic cells (DCs) promoted radiation-induced antitumor immunity by enhancing the cross-priming activity of DCs. Overall, we demonstrated that radiation-induced activation of the AIM2 and NLRP3 inflammasomes coordinate to induce some of the antitumor effects of radiation by triggering IL-1 signaling in DCs, leading to their activation and cross-priming.
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Park, Jun Young, Yeo Wool Kang, and Won Gil Cho. "Inflammasome-Mediated Inflammation in Neurodegenerative Diseases." Open Neurology Journal 13, no. 1 (April 17, 2019): 55–62. http://dx.doi.org/10.2174/1874205x01913010055.
Full textAbstract:
Inflammasomes are protein platforms consisting of multiple proteins. The biological function includes the activation of caspase-1, leading to the maturation of IL-1β and IL-18. These pro-inflammatory cytokines promote fundamental inflammatory processes in numerous infectious diseases. The inflammasome-mediated inflammation has become increasingly important in central nervous system disorders. In neurodegenerative disorders, significant contributors to disease progression include neuroinflammation and inflammatory cascades initiated by the inflammasome protein complex. This review discusses the recent progress of research on inflammasome associated with neurodegenerative disorders.
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Yerramothu, P., A. K. Vijay, and M. D. P. Willcox. "Inflammasomes, the eye and anti-inflammasome therapy." Eye 32, no. 3 (November 24, 2017): 491–505. http://dx.doi.org/10.1038/eye.2017.241.
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Li, Yueying, Yuntao Liu, Xia Yan, Qing Liu, Yong-Hua Zhao, and Da-Wei Wang. "Pharmacological Effects and Mechanisms of Chinese Medicines Modulating NLRP3 Inflammasomes in Ischemic Cardio/Cerebral Vascular Disease." American Journal of Chinese Medicine 46, no. 08 (January 2018): 1727–41. http://dx.doi.org/10.1142/s0192415x18500878.
Full textAbstract:
Cardio/cerebral-vascular diseases seriously threaten human health and are the leading cause of death. As such, there is great interest in identifying a potential mechanism that controls the development process of cardio/cerebral vascular diseases. Present studies demonstrate that inflammasomes play an important role in the process of ischemic cardio/cerebral vascular diseases (ICCVDs). Among the pathological process of ICCVDs, inflammasomes activated the sterile inflammatory response that accelerated the development of diseases and aggravated the acute lesion of tissue. As the most thoroughly studied inflammasome, the NLRP3 inflammasome has been proven to be a potential therapeutic target for ICCVDs. In this review, we summarized the mechanisms of Chinese herbal medicine which can affect ICCVDs via the regulation of the NLRP3 inflammasome. Our study discovers that active compounds of Chinese medicines have a negative effect on NLRP3 in different ICCVDs models. Astragaloside IV may influence the receptor of the cell membrane to inhibit NLRP3 activation. Resveratrol, colchicinesis, salvianolic acid B, chrysophanol and sulforaphane may directly damage the formation of NLRP3 by inhibiting ASC or Caspase-1. Most of the active natural compounds can negatively regulate the downstream products of NLRP3 inflammasome such as IL-18 and IL1[Formula: see text]. In addition, Chinese medicines such as sinomenine, ruscogenin, resveratrol, arctigenin and cepharanthineas may downregulate NLRP3 inflammasome by inducing autophagy activation. Due to the advantages of multi-target effects, Chinese herbal medicine can be treated as a splendid therapy for ICCVDs by inhibiting NLRP3 inflammasome.
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Hori, Juliana I., Dario S. Zamboni, Daniel B. Carrão, Gustavo Henrique Goldman, and Andresa A. Berretta. "The Inhibition of Inflammasome by Brazilian Propolis (EPP-AF)." Evidence-Based Complementary and Alternative Medicine 2013 (2013): 1–11. http://dx.doi.org/10.1155/2013/418508.
Full textAbstract:
Propolis extracts have gained the attention of consumers and researchers due to their unique chemical compositions and functional properties such as its anti-inflammatory activity. Recently, it was described a complex that is also important in inflammatory processes, named inflammasome. The inflammasomes are a large molecular platform formed in the cell cytosol in response to stress signals, toxins, and microbial infections. Once activated, the inflammasome induces caspase-1, which in turn induces the processing of inflammatory cytokines such as IL-1βand IL-18. So, to understand inflammasomes regulation becomes crucial to treat several disorders including autoinflammatory diseases. Since green propolis extracts are able to regulate inflammatory pathways, this work purpose was to investigate if this extract could also act on inflammasomes regulation. First, the extract was characterized and it demonstrated the presence of important compounds, especially Artepillin C. This extract was effective in reducing the IL-1βsecretion in mouse macrophages and this reduction was correlated with a decrease in activation of the protease caspase-1. Furthermore, we found that the extract at a concentration of 30 μg/mL was not toxic to the cells even after a 18-hour treatment. Altogether, these data indicate that Brazilian green propolis (EPP-AF) extract has a role in regulating the inflammasomes.
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Sharma, Deepika, and Thirumala-Devi Kanneganti. "The cell biology of inflammasomes: Mechanisms of inflammasome activation and regulation." Journal of Cell Biology 213, no. 6 (June 20, 2016): 617–29. http://dx.doi.org/10.1083/jcb.201602089.
Full textAbstract:
Over the past decade, numerous advances have been made in the role and regulation of inflammasomes during pathogenic and sterile insults. An inflammasome complex comprises a sensor, an adaptor, and a zymogen procaspase-1. The functional output of inflammasome activation includes secretion of cytokines, IL-1β and IL-18, and induction of an inflammatory form of cell death called pyroptosis. Recent studies have highlighted the intersection of this inflammatory response with fundamental cellular processes. Novel modulators and functions of inflammasome activation conventionally associated with the maintenance of homeostatic biological functions have been uncovered. In this review, we discuss the biological processes involved in the activation and regulation of the inflammasome.
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Boini, Krishna M., Tahir Hussain, Pin-Lan Li, and Sai S. Koka. "Trimethylamine-N-Oxide Instigates NLRP3 Inflammasome Activation and Endothelial Dysfunction." Cellular Physiology and Biochemistry 44, no. 1 (2017): 152–62. http://dx.doi.org/10.1159/000484623.
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Background/Aim: Plasma trimethylamine-N-oxide (TMAO), a product of intestinal microbial metabolism of dietary phosphatidylcholine has been recently associated with atherosclerosis and increased risk of cardiovascular diseases (CVD) in rodents and humans. However, the molecular mechanisms of how TMAO induces atherosclerosis and CVD progression are still unclear. The present study tested whether TMAO induces NLRP3 inflammasome formation and activation and thereby contributes to endothelial injury initiating atherogenesis. Methods: Inflammasome formation and activation was determined by confocal microscopy, caspase-1 activity was measured by colorimetric assay, IL-1β production was measured using ELISA, cell permeability was determined by microplate reader and ZO-1 expression was determined by western blot analysis and confocal microscopy. In in vivo experiments, TMAO was infused by osmotic pump implantation. Results: TMAO treatment significantly increased the colocalization of NLRP3 with Asc or NLRP3 with caspase-1, caspase-1 activity, IL-1β production, cell permeability in carotid artery endothelial cells (CAECs) compared to control cells. Pretreatment with caspase-1 inhibitor, WEHD or Nlrp3 siRNA abolished the TMAO-induced inflammasome formation, activation and cell permeability in these cells. In addition, we explored the mechanisms by which TMAO activates NLRP3 inflammasomes. TMAO-induced the activation of NLRP3 inflammasomes was associated with both redox regulation and lysosomal dysfunction. In animal experiments, direct infusion of TMAO in mice with partially ligated carotid artery were found to have increased NLRP3 inflammasome formation and IL-1β production in the intima of wild type mice. Conclusion: The formation and activation of NLRP3 inflammasomes by TMAO may be an important initiating mechanism to turn on the endothelial inflammatory response leading to endothelial dysfunction.
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McCarty, Mark F., Simon Bernard Iloki Assanga, Lidianys Lewis Luján, James H. O’Keefe, and James J. DiNicolantonio. "Nutraceutical Strategies for Suppressing NLRP3 Inflammasome Activation: Pertinence to the Management of COVID-19 and Beyond." Nutrients 13, no. 1 (December 25, 2020): 47. http://dx.doi.org/10.3390/nu13010047.
Full textAbstract:
Inflammasomes are intracellular protein complexes that form in response to a variety of stress signals and that serve to catalyze the proteolytic conversion of pro-interleukin-1β and pro-interleukin-18 to active interleukin-1β and interleukin-18, central mediators of the inflammatory response; inflammasomes can also promote a type of cell death known as pyroptosis. The NLRP3 inflammasome has received the most study and plays an important pathogenic role in a vast range of pathologies associated with inflammation—including atherosclerosis, myocardial infarction, the complications of diabetes, neurological and autoimmune disorders, dry macular degeneration, gout, and the cytokine storm phase of COVID-19. A consideration of the molecular biology underlying inflammasome priming and activation enables the prediction that a range of nutraceuticals may have clinical potential for suppressing inflammasome activity—antioxidants including phycocyanobilin, phase 2 inducers, melatonin, and N-acetylcysteine, the AMPK activator berberine, glucosamine, zinc, and various nutraceuticals that support generation of hydrogen sulfide. Complex nutraceuticals or functional foods featuring a number of these agents may find utility in the prevention and control of a wide range of medical disorders.
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Murthi, Padma, and Gayathri Rajaraman. "Inflammasomes in the Pathophysiology of Maternal Obesity: Potential Therapeutic Targets to Reduce Long-Term Adverse Health Outcomes in the Mother and Offspring." Current Vascular Pharmacology 19, no. 2 (December 30, 2020): 165–75. http://dx.doi.org/10.2174/1570161118666200603131536.
Full textAbstract:
: Over the past 20 years, the prevalence of obesity has risen dramatically worldwide, with an increase in occurrence among women in their reproductive age. Obesity during pregnancy is associated with significantly increased maternal and fetal morbidity and mortality. In addition to the short-term adverse health outcomes, both mother and the child are prone to develop cardiovascular, metabolic and neurological disorders. Although associations between obesity during pregnancy and adverse maternalfetal health outcomes are clear, the complex molecular mechanisms underlying maternal obesity remain largely unknown. This review describes multimeric self-assembling protein complexes, namely inflammasomes, as potential molecular targets in the pathophysiology of maternal obesity. Inflammasomes are implicated in both normal physiological and in pathophysiological processes that occur in response to an inflammatory milieu throughout gestation. This review highlights the current knowledge of inflammasome expression and its activity in pregnancies affected by maternal obesity. Key discussions in defining pharmacological inhibition of upstream as well as downstream targets of the inflammasome signaling cascade; and the inflammasome platform, as a potential therapeutic strategy in attenuating the pathophysiology underpinning inflammatory component in maternal obesity are presented herein.
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Zhou, Keren, Ligen Shi, Yan Wang, Sheng Chen, and Jianmin Zhang. "Recent Advances of the NLRP3 Inflammasome in Central Nervous System Disorders." Journal of Immunology Research 2016 (2016): 1–9. http://dx.doi.org/10.1155/2016/9238290.
Full textAbstract:
Inflammasomes are multiprotein complexes that trigger the activation of caspases-1 and subsequently the maturation of proinflammatory cytokines interleukin-1βand interleukin-18. These cytokines play a critical role in mediating inflammation and innate immunity response. Among various inflammasome complexes, the NLRP3 inflammasome is the best characterized, which has been demonstrated as a crucial role in various diseases. Here, we review recently described mechanisms that are involved in the activation and regulation of NLRP3 inflammasome. In addition, we summarize the recent researches on the role of NLRP3 inflammasome in central nervous system (CNS) diseases, including traumatic brain injury, ischemic stroke and hemorrhagic stroke, brain tumor, neurodegenerative diseases, and other CNS diseases. In conclusion, the NLRP3 inflammasome may be a promising therapeutic target for these CNS diseases.