Inflammasome function To truly comprehend NLRP3-ASC specks, advanced techniques are necessary to evaluate colocalization, modulate activation thresholds, and investigate non-inflammasome functions. Unlike myeloid cells where NLRP3 is cytosolic, NLRP3 is localized to the nucleus in T Although NLRP3 inflammasome functions have been extensively studied, and the immunomodulatory effect of caffeine has been known for a while, the potential modulatory role of caffeine on the NLRP3 inflammasome-mediated IL-1β production on various macrophage populations has not been reported before. While NLRP3 inflammasome is assumed as key regulator for innate and adaptive immune responses, and has been associated with various pathological events, the precise impact of the nuclear receptors on the function of inflammasome is hardly investigated. Specifically, Nlrp3-deficient mice exhibited reduced tumor growth compared to wild-type animals and induction of robust anti-tumor immunity, accompanied by re-wiring of the MDSC compartment. NLRP3 was found to be expressed in differentiated T helper cell subsets and specifically control Th2 cell differentiation. It is crucial that pathogens While not required and insufficient for NLRP3 inflammasome function, the NLRP3:ASC speck is a dynamic, spatially, and temporally distinct structure regulated in part by caspase-1. In contrast, NAIP and NLRC4 form a single inflammasome cooperatively as sensor (NAIP) and adaptor (NLRC4) proteins. 217 Later, pyrin was shown to sense inactivation of the RhoA GTPase mediated by bacterial toxins, 135 solidifying its role as an We develop an operative framework for inflammasome function and regulation by host cell factors and pathogens. The priming and activation of the NLRP3 inflammasome is a major trigger for inflammation which is a defense response against adverse stimuli. It remains to be established whether the low inflammasome function could contribute to loss of tolerance and the onset of Furthermore, imeglimin restored the mitochondrial function by modulating mitochondrial membrane depolarization and mPTP opening. In turn, ESX-1-mediated activation of the cytosolic inflammasome sensors NLRP3 and AIM2 leads to Glibenclamide (GLB) reduces brain edema and improves neurological outcome in animal experiments and preliminary clinical studies. In the Schematic representation of the different functions of NLPR6 in a the digestive system, b joints, c lungs, d oral cavity, e cancer, f liver, g peripheral and central nervous system, and h kidney. . [PMC free article] [Google Scholar] 101. Gasdermin B, a substrate of both inflammatory and apoptotic caspases, was Various receptors also function in inflammasome activation in different cellular compartments, including the cytoplasm and the nucleus. However, in certain circumstances, inflammasome signaling is beneficial in infections and can also impede tumor growth. 45, 46 These findings are worth considering while developing The main function of the CARD8 inflammasome seems to be to trigger pyroptosis 53,55,56. The formation of autophagosome is a feature of autophagy. The NOR test was performed at 2 and 24 h delay after the familiar phase to assess both short- and long-term non-spatial, hippocampal-mediated recognition memory. Methods: First, Western blot analysis was used to detect the expression levels of NLRP3, ASC, pro-IL-1β and cleaved IL-1β, and RT-qPCR was used to detect the mRNA expression levels of them. Yet despite their protective role, aberrant activation of inflammasome proteins and gain of function mutations in inflammasome c Inhibition of NLRP3 inflammasome with MCC950 improves functional outcome after CA/CPR. Caspase-1, a crucial player in inflammasome function, was abundantly present in CD1c+ mDCs and CD16+ cells but was lacking in pDCs (Figure 6A). of the inflammatory cytokines in macrophages and monocytes,indicatethedifferencesintheirfunctions. The effectiveness of inflammasomes at suppressing virus replication is highlighted by the prevalence and diversity of virus encoded inflammasome inhibitors. The NLRP3 Inflammasome activation mechanisms in the CNS are distinct from those characterized in peripheral immune cells. , FXR-SHP axis). A screening of more than Recent studies have offered a glimpse into the sophisticated mechanisms by which inflammasomes respond to danger and promote secretion of interleukin (IL)-1β and IL-18. AJRCCM Home; AJRCMB Home; AnnalsATS Home; ATS Documents; Podcasts; Services. Through the increased generation of ROS, this cyclic interaction raises oxidative stress, encourages chronic inflammation, and causes cell malfunction, which ultimately results in issues with reproductive health However, recent studies reported that K + efflux occurs through the GSDMD pores generated by caspase‐11 non‐canonical inflammasome‐processed N‐terminal GSDMD fragments, resulting in the activation of NLRP3 inflammasome. 4of29 DAIetal. Deregulation of its activity leads to many inflammatory disorders including gouty arthritis, Alzheimer disease, and cancer. Loss of cellular potassium is known to potently suppress protein synthesis, leading us to test whether the inhibition of protein synthesis itself serves as an activating signal for the NLRP3 inflammasome. Med. 1. Activated caspase-1 subsequently leads to the maturation of IL-1β and IL The activity of the inflammasome, a multi-protein complex that amplifies immune reactions to both foreign and endogenous activators, is one of the primary inflammatory processes that result in the occurrence of inflammatory disorders including cancer [10, 41, 42]. CARD, caspase recruitment domain; FIIND, domain with function to find; LRR, leucine-rich repeat; NACHT, nucleotide-binding and oligomerization domain; NLR, Nod-like receptor; PYD, pyrin. Recent studies have highlighted the intersection of this inflammatory response with fundamental cellular processes. Specifically, we focus on the triggers of inflammasome activation in alcoholic steatohepatitis and NASH, chronic HCV infection, ischaemia-reperfusion injury and paracetamol-induced Although its role in inflammasome formation was debated for many years, 214, 215, 216 missense mutations linked to FMF in pyrin led to gain-of-function inflammasome activation in mice independent of NLRP3. Furthermore, the speck lowers the Although its role in inflammasome formation was debated for many years, 214, 215, 216 missense mutations linked to FMF in pyrin led to gain-of-function inflammasome activation in mice independent of NLRP3. Xiaorong Zhu a Department of Hematology, a large number of clinical studies and functional experiments on NLRP3 inflammasomes are activated by LPS and ATP in vitro and then the correlation between NLRP3 inflammasomes and the pathogenesis of various diseases is further studied. Activated caspase-1 subsequently leads to the maturation of IL-1β and IL It is generally thought that effective NLRP3 inflammasome function requires both ‘priming’ and activation, as described above (Figure 2); however, a recent study found that a priming step may be dispensable in human monocytes, but essential in monocyte‐derived macrophages. Ting, in Inflammasome Biology, 2023. Cell surface-expressed TLRs and CLRs as well as cytosolic NLRs (NOD2) induce up-regulation of IL1B and NLRP3 mRNA following recognition of Mtb-derived molecules. Inflammasome-independent functions of AIM2 in microglia and T reg cells. 67 Titanium dioxide, used as a food additive and in pharmaceutical formulations, aggravates DSS-induced A currently unknown cytosolic LPS sensor mediates activation of caspase-11 in the noncanonical inflammasome. In this Review, we discuss the different types of inflammasomes, their activation and biological functions in the context of liver injury and disease progression. Briefly, inflammasome‐inducing stimuli trigger the NLRP3 inflammasome is a multiprotein complex expressed in a variety of cells to stimulate the production of inflammatory factors. We report a homeostatic function of the We showed that exons 4,5,7 and 9 are essential for inflammasome function, both in the context of wild type NLRP3 activation by the agonist molecule nigericin and in a model of CAPS-mediated NLRP3 Therefore, NLR inflammasome sensors could, in fact, function as adaptor molecules rather than receptors. However, for several year, the work of different teams has proven that NLRP3 is also expressed in other cell types where it has functions that are independent of the inflammasome. Youm YH, et al. Whilst much work has been performed in animal models, to date there is limited evidence of the role and function of the inflammasome in human tissue. Mechanistically, pharmacological inhibition of mtROS markedly attenuated inflammasome activation. Canonical activation of the inflammasome is critical to promote caspase-1-dependent maturation of the proinflammatory cytokines IL-1β and IL-18, as well as to induce pyroptotic cell death in response to pathogens and endogenous danger signals. Understanding these mechanisms accentuates the NEK7 belongs to a family of kinases that also include NEK9. We will examine the mechanisms involved in the epigenetic regulation of ASC NLRP3 functions have mainly been studied in the context of the inflammasome, in myeloid cells and in totally deficient transgenic mice. Our data show that inflammasome function, through the NLRP3–ASC Key studies published in the last few years have expanded the knowledge on pyrin inflammasome activation and function. Unlike myeloid cells where NLRP3 is cytosolic, NLRP3 is localized to the nucleus in T cells and lacks Some inflammatory stimuli trigger activation of the NLRP3 inflammasome by inducing efflux of cellular potassium. First recognized for their role in host defense, inflammasomes play crucial roles in contributing to and often instigating the development of inflammatory, A key function of a subgroup of NLR proteins is to mediate inflammasome function. The priming signal (signal 1, left) is provided by microbial components or endogenous cytokines, leading to the activation of the transcription factor NF-κB and subsequent upregulation of NLRP3 and pro-interleukin-1β (pro-IL-1β). Activation and assembly of the inflammasome promotes the activation of Inflammasome is a protein complex that plays an important role in innate immunity and body's response to attacks from both pathogens and endogenous dangers signals. We demonstrated for the first time that imeglimin reduces LPS-induced NLRP3 inflammasome activation by inhibiting mPTP opening in THP-1 macrophages. Whereas its role in the context of cancer has been mostly explored in the immune compartment, whether NLRP3 exerts Inflammasomes, cytosolic multicomponent complexes, sense patterns of pathogenesis or metabolic changes and initiate a cellular response via the activation of the inflammatory caspases (iCasps) (1–3). インフラマソーム（英: inflammasome ）は細胞質に位置する多タンパク質オリゴマーであり、自然免疫系に関与し、炎症応答の活性化を担う [1] [2] 。インフラマソームの活性化と組み立ては、炎症性サイトカインであるIL-1βとIL-18の切断、成熟、分泌、そしてガスダーミン The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer. While inflammasomes influence the innate and adaptive immune components’ interplay modulating the anti-pathogen adaptive immune response, pathogens may target inflammasome inhibition as a survival strategy. The formation of the inflammasome enables activation of an inflammatory protease caspase-1, pyroptosis initiation with the subsequent cleaving of the pro-inflammatory cytokines Activation of the inflammasome is a key event in inflammatory immune response. 76, 77, 78 The purpose of this study was to demonstrate a novel function of GSDMD as an agonist of the NLRP3 The view that the NLRP3 inflammasome has a protective role in colitis, supported by the studies described above, is challenged by other studies showing that loss of this inflammasome function is associated with decreased Our data, which highlight differential requirements for caspase-1 autoproteolysis in NLRP1b and NLRP3 inflammasome function, may have implications for pathogen recognition and response. 1 Introduction. Our data, which highlight differential requirements for caspase-1 autoproteolysis in NLRP1b and NLRP3 inflammasome function, may have implications for pathogen recognition and response. The inflammasomes are cytosolic multiprotein complexes that are composed of an inflammasome-initiating sensor, apoptosis-associated speck-like protein containing a CARD (ASC) acts as an adaptor protein and the protease-caspase-1. However, the aberrant activation of the NLRP3 inflammasome has been linked with several inflammatory disorders, which include NLR family pyrin domain containing 3 (NLRP3) (previously known as NACHT, LRR, and PYD domains-containing protein 3 [NALP3] and cryopyrin), is a protein that in humans is encoded by the NLRP3 gene [5] located on the long arm of chromosome 1. NLRP3 Last, inflammasome-independent functions in tumor promotion have been reported. The cleansing of cell debris via the inflammasome-induced recruitment of phagocytes could prevent chronic inflammation (Fig. Assembly of inflammasomes can occur at the mitochondria, endoplasmic reticulum, nucleus, trans-Golgi network, or pathogen surface, facilitated by the overarching architecture of the cytoskeleton. 207, 1045–1056 (2010). Inflammasome is the upstream promoter for pyroptosis, which Inflammasome effector functions: a Tale of Fire and Ice. A screening of more than In this Review, we summarize our current understanding of the structures of inflammasome components and how these structures relate to their functions — focusing on NAIP–NLRC4, NLRP3, NLRP1 However, Chae et al. 2010;207:1045–1056. However, there is currently no known functional connection between complement and caspase activation, and the focus in this review will thus be on the functional connection between complement and canonical inflammasome activation. The assembly and activation of NLRP3 inflammasome results in caspase-1 activation. The NLRP1 inflammasome is regulated through a unique process of functional degradation, while the Pyrin inflammasome senses the inactivation of other host proteins (Fig. Regulatory mechanisms that potentiate or limit inflammasome activation are examined, as well as emerging links between the Therefore, the Nlrp3 inflammasome is functional both in immune cells and in HSPCs and affects hematopoiesis in either a positive or negative way, depending on its activity level. Here, we review the structure, biological functions, and therapeutic targets of inflammasomes, while highlight The NOD-like receptor protein 3 (NLRP3) inflammasome is a protein complex that regulates innate immune responses by activating caspase-1 and the inflammatory cytokines interleukin (IL)-1β and IL-18. Pilot structure-function studies revealed that the cyclohexylurea group is Inflammasomes are multimeric protein complexes that can detect various physiological stimuli and danger signals. Irradiated mice of indicated genotypes were grafted with bone marrow stem cells from WT or Caspase-1 KO mice and were injected with 4T1 mammary tumor cells 28 days later. New York, NY 10004 (212) 315-8600. A landmark advance in the inflammasome field was the discovery that pyroptosis is driven by inflammatory caspase-mediated cleavage of gasdermin D (GSDMD) (11–13). Notably, long-term sustained inhibition of NLRP3 inflammasome may impair normal immune function in the body, which may ultimately produce irreversible damage. The CARD domain can either directly interact with caspase-1 or via the CARD domain of ASC. Inflammasomes are multiprotein complexes assembled in response to pathogen- and damage-associated molecular patterns (PAMPs and DAMPs) and cellular stress. The major inflammatory mediators include IL-1 family members, such as IL-1β, and the functional As NLRP3 has non-canonical inflammasome and inflammasome-independent PRR functions in addition to its role in the canonical inflammasome pathway, targeting the NLRP3 inflammasome upstream of The presence of the inflammasome in the hematopoietic compartment promotes mammary tumor growth. We report that a hallmark of MDSs is activation of the NLRP3 inflammasome, which drives clonal expansion and pyroptotic cell death. doi: 10. Fig. In addition, post-translational modifications of NLRs, such as phosphorylation 67, The NZW parental strain showed strong inflammasome function, whereas the NZB/W F1 have haploinsufficient expression of NLRP3 and show reduced NLRP3 and AIM2 inflammasome responses, particularly at low stimulus strength. In addition to recently discovered role of PELO in the inflammasome assembly, this gene product regulates translation and ribosome disassembly, stem cells population Transfer RNA (tRNA) Methylation Preserves Inflammasome Function During Cellular Stress (abstract). Am J Respir Crit Care Med 2024;209:A6835. In this review, we explored the biological properties of the NLRP3 inflammasome and the role and research progress of the NLRP3-mediated pyroptosis in sterile arthritis. It is a multimeric complex composed of a variety of proteins, in particular, comprising of Organelles are critical structures in mediating the assembly and activation of inflammasomes in mammalian cells, resulting in inflammation and cell death. Autophagy is a physiological process that maintains the normal metabolic function and survival of cells. This is in contrast to the NLRP3 inflammasome activity, which is inhibited in the absence of caspase-1 autoproteolyis. Caspase-1 in turn regulates the proteolytic maturation of interleukin-1β and IL Cell-intrinsic inflammasome regulation. Activation of caspases 1 and 11 in canonical and noncanonical inflammasomes, respectively, also protects against infection by trigg NLRP3 inflammasome: structure and function. Investigations into these cell types revealed an ability of NLRP1 to sense the protease activity of picornaviruses, leading to inflammasome activation, 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. In microglia, AIM2 forms a complex with Meanwhile, we found that USP14 selectively suppressed NLRP3 protein degradation through the USP motif on the NACHT domain in mediating inflammasome activation. Since the inflammasome-associated cytokine IL-1β acts as a master regulator of distinct physiological functions [16], inflammasome activation has been inextricably linked to IL-1β-initiated signaling. In the context of tumorigenesis, several NLRs contribute to tumor progression by their ability to modulate the inflammatory response, creating a tumor Additional epithelial cell types that execute inflammasome functions are primary human airway epithelial cells and the human keratinocyte cell line HaCaT. Tight regulation of the NLRP6 inflammasome is critical in maintaining tissue homeostasis, while improper NLRP3 inflammasome biology Structure and function. Although considered the ternary inflammasome structure, whether the singular, perinuclear NLRP3:ASC speck is synonymous with the NLRP3 inflammasome is unclear. Murine bone marrow-derived macrophages, Here, we comprehensively review mechanisms directing normal inflammasome function and its dysregulation in disease. Consequently, the inflammasome plays a key role in protecting the host from pathogens, but aberrant activation can also lead to conditions such as gout, diabetes, and liver Whereas the inflammasome and its functions were initially described in immune cells and studies in alcoholic steatohepatitis suggest a specificity for Kupffer cells, 18,86 the role of the NLRP3 Here, we comprehensively review mechanisms directing normal inflammasome function and its dysregulation in disease. Also, the host has a myriad of regulatory mechanisms A Two-Signal Model for NLRP3 Inflammasome Activation. Circulating levels of IL-1β were elevated in Sjögren’s syndrome (), but not in autoimmune hemolytic anemia (). Exp. When the function of a cell is compromised or the survival of the cell poses a danger to the whole organism, it should be eliminated. One of the objectives of this However, the interdependency of each pathway needs further investigations as results from Viaud et al. Nowadays, FXR ligands are under clinical trials targeting human metabolic dysregulation-associated diseases; such as obesity, type 2 diabetes, or liver diseases . The NLRC4/NAIP5 inflammasome, together with TLR5 in macrophages, recognizes overexpressed flagellin in tumor cells, leading to tumor clearance by the innate immune response and tumor-specific, CD4 + and CD8 + T cells in vivo (Garaude et al. Among inflammasomes, NLRP3 – also known as cryopyrin - is the most widely and comprehensively characterized. 3). They are formed as a result of specific cytosolic pattern recognition receptors (PRRs) sensing microbe-derived pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs) from the host cell, or homeostatic disruptions. Reported levels of IL-1β in systemic lupus erythematosus (SLE) patient serum range from undetected (17, 18), decreased in SLE relative to controls (19, 20), to Inflammasome complexes and their integral receptor proteins have essential roles in regulating the innate immune response and inflammation at the post-translational level. In this section, we consider the consequences of microglial NLRP3 inflammasome Background The NLRP3 inflammasome is a vital player in the emergence of inflammation. , 2012). The inflammasome plays multifaceted roles in cancer, but less is known about its function during premalignancy upon initial cell transformation. In the BDCA3+ mDC-enriched sample, caspase-1 was present but at much lower levels than in CD1c+ mDCs. The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer. NF-κB is a central mediator of the priming signal of NLRP3 inflammasome activation and acts by inducing the transcriptional expression of NLRP3 and pro-IL-1β in response to various PRR ligands Heavy metals disrupt mitochondrial function and activate the NOD‐like receptor pyrin‐containing 3 (NLRP3) inflammasome. Although caspase-8 can function as an IL-1β-converting enzyme in certain circumstances, in many of these cases caspase-8 interacts with the NLRP3 inflammasome to modulate inflammasome effector functions, especially in the absence of caspase-1. [6]NLRP3 is expressed predominantly in macrophages and as a component of the inflammasome, [7] [8]: 436 detects NLRP3 is a pattern recognition receptor with a well-documented role in inducing inflammasome assembly in response to cellular stress. The Journal of experimental medicine. The contribution of non-canonical inflammasome to sepsis has been reported in septic mice model (7, 37–39). showed that while polydA:dT stimulation of three NSCLC cell-lines activated the AIM2 inflammasome, it did not have an impact on their growth or survival. Caspase-8, an apoptotic caspase, has emerged as a key player in the regulation of inflammation and inflammasome functions. 20100050. Inflammasome activation in macrophages is an early event occurring at the initiation of an inflammatory response. Despite a proliferation of review articles compared with research articles in recent years, there is a need to focus efforts on examining the role of the inflammasome in human conditions. Agonists and activation mechanisms of the NLRP1, NLRP3, IPAF, and AIM2 inflammasomes are discussed. 25 Broadway. 3: Activation of The NLRP3 inflammasome functions as a driver of the myelodysplastic syndrome phenotype. This work was triggered by the discovery that RhoA inactivation serves a signal for pyrin activation, and facilitated the finding of the protein kinases (PKN1/2), a downstream targets of RhoA, that are responsible for the pyrin Objective: The drug resistance of multiple myeloma (MM) cells is one of the main causes of relapse, refractory and progression of MM. Canonical Nlrp3 inflammasome links systemic low-grade inflammation to functional decline in Research over the past ten years has greatly improved the understanding of the function of the NLRC4 inflammasome, showing their function is not limited to immune recognition but rather their wider involvement in the regulation of immune responses. Thus, caspase-1 and -8 act as effectors of inflammasome signaling. The NLRP3 inflammasome plays a crucial role in various metabolic Hence, the importance of ROS in NLRP3 inflammasome function has been widely acknowledged, but the exact mechanism remains to be explored. Different DAMPs and PAMPs are able to induce NLRP3, while NLRP1b responds to Bacillus anthracis lethal toxin, NLRC4 recognizes bacterial flagellin and/or the type III secretion system of bacterial pathogens, AIM2 is specifically activated by dsDNA, and pyrin recognizes the inactivation of RhoA by toxins and effector AIM2 was found to be activated in an inflammasome-dependent way to release IL-1beta and IL-18 to mediate inflammation, and to participate in immune regulation in psoriasis, or in an inflammasome-independent way by regulating the function of regulatory T cells or programming cell death in keratinocytes as well as controlling the proliferative Inflammasome function has been proposed to contribute to autoimmunity (13, 14). Advertising and Recruitment; Press Releases; Inflammasomes are cytosolic multiprotein complexes which upon assembly activate the pro‐inflammatory caspase‐1 (see Glossary) that is responsible for the maturation and secretion of the inflammatory cytokines IL‐1β and IL‐18, and additionally induce pyroptosis (Lamkanfi & Dixit, 2014; Broz & Dixit, 2016). It isalsoworthnotingthatcaspase-8,thedeterminantof The gain-of-function mutations in inflammasome components are also known to cause cryopyrin-associated periodic syndrome (CAPS), a group of congenital diseases characterized by IL-1β-mediated systemic inflammation. 1084/jem. Data represent Herein, we demonstrate an important role of NLRP3 inflammasome in the functional properties of MDSCs in tumor-bearing hosts. Inflammasomes are large multimolecular complexes best known for their ability to control activation of the proteolytic enzyme caspase-1 (Martinon et al. 2020). Cleavage of GSDMD relieves an autoinhibited state, leading to assembly of a multimeric GSDMD pore in the plasma membrane and release of cytoplasmic molecules (14, 15). The main function of NLRP3 inflammasome‐driven caspase‐1 activation is the subsequent conversion of inactive The inflammasome is a multiprotein complex that mediates the activation of caspase-1, which promotes secretion of the proinflammatory cytokines interleukin 1β (IL-1β) and IL-18, as well as Nutrition as a modulator of NLRP3 inflammasome activation Dietary constituents, such as saturated fatty acids, can function as stimuli for inflammasome activation to elicit endoplasmic reticulum stress responses, including IRE1α activation. (A) Tumor growth was measured over 30 days. While the initial discovery of the Targeting these epigenetic mechanisms could be a valuable strategy for restoring inflammasome homeostasis and maintaining a balance between inflammasome function in consequence to environmental signals and the prevention of tissue damage caused by their uncontrolled activation (Poli et al. As a result, they perform a crucial function in the innate immune response. Independent of genotype, MDS hematopoietic stem and progenitor cells (HSPCs) overexpress inflammasome proteins and Notably, a higher inducibility of NLRP3 inflammasome activation in response to ATP and nigericin following challenge with lipopolysaccharide (LPS) was observed in BACH1-deficient macrophages compared to wild-type cells. NLRP3 Inflammasome signalling in brain function and neurodegenerative disease Nat Rev Neurosci. Inflammasomes are large intracellular multi-protein signalling complexes that are formed in the cytosolic compartment as an inflammatory immune response to endogenous danger signals. Here, we described for the first time the NLRP3 inflammasome: structure and function. In contrast, AIM2 promoted NSCLC tumor growth in vivo by regulating mitochondrial fusion dynamics and ERK The inflammasome is defined as a group of cytosolic multiprotein complexes involving NLR proteins and caspase-1, which can induce various biological responses such as depression-like behavior and neuronal apoptosis in the context of neuroscience. The NLRP3 inflammasome mainly consists of the cytosolic sensor molecule NLRP3, the adaptor protein ASC, and the effector molecule pro-caspase-1. In this review, we will discuss the recent progress on the regulation of the AIM2 inflammasome and its biological functions in sterile inflammatory diseases, infectious diseases and cancer. Two divergent mechanisms have been reported for the regulatory roles of AIM2 during neuroinflammation. NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) is an intracellular complex that upon external stimuli or contact with specific ligands, recruits other components, forming the NLRP3 inflammasome. 36–43 NEK7 interacts with NEK9 during mitosis and serves as a molecular switch that dictates the mutual exclusivity between NLRP3 inflammasome activation and cytokinesis. C57BL/6 mice encode four functional Naip (neuronal apoptosis An inflammasome-independent function has also recently been proposed for the NLRP3 inflammasome (Bruchard et al. The active inflammasome then triggers caspase-1 activation, followed by the The inflammasomes are innate immune system receptors/sensors that regulate the activation of caspase-1 and induce inflammation in response to infectious microbes and molecules derived Inflammasomes activate inflammatory caspases, cysteine-dependent aspartate-directed proteases, which promote the maturation of the cytokines interleukin-1β (IL-1β) and IL Here, we review recent progress in our understanding of inflammasome signaling, the consequences of aberrant inflammasome signaling in human disease, and the therapeutic The wide range of the stimuli makes the function of inflammasome diverse and complex. J. Herein, we report that the NLRP3:ASC speck is not required for nigericin-induced inflammasome activation but facilitates and maximizes IL-1β While details of the inflammasome pathway have been deeply studied, much less is known about the functional consequences of inflammasome activation in immune cells on other cell types in the brain and the signaling pathways altered in these other cell types. The authors also highlight the latest development on the regulation of the inflammasome, in particular, the role of Syk and caspase-8 in shaping the immunological profile during fungal infection. The Crosstalk between NLRP3 and Autophagy. We investigated the effect of lead (Pb)/cadmium (Cd) on mitochondrial An outstanding question is how NLR functions, inflammasome-dependent and independent, impact on the underlying mucosal-associated lymphoid tissue (MALT). The NLRP3 inflammasome, as a vital constituent of the inflammasome family, is significant in defending against In addition to investigating the inflammasome-associated role of ASC specks, it is equally important to explore potential non-inflammasome functions of these structures. 2). Inflammasomes, formed by sensor proteins such as NLRP3, assemble in response to However, it is not known whether the ASC/TMS1-dependent epigenetic regulation controls the inflammasome functions and moreover whether this regulation has any role in the inflammation-mediated carcinogenesis or in the pathogenesis of age-related degenerative diseases. In addition, the apoptosis caspase CASPASE-3 can cleave GSDME in response to chemotherapy to trigger cancer cell NLRP3 inflammasome activation is largely triggered by oxidative stress, and inflammasome activity also affects mitochondrial function. NLR-mediated inflammasome activation is important in host response not only to bacteria, fungi, viruses, and possibly parasites, but also to DAMPs . The link between altered inflammatory mediators and changes in mucosal immune responses in the context of IEC-specific deletion of NLR proteins has been little studied. NLRP3 was found to be expressed in differentiated T helper cells subsets and specifically control Th2 cell differentiation. 27 The molecular Function of NLRP3 inflammasome activation in multiple myeloma. The functional consequences of inflammasome activation are ultimately determined by the substrate specificity of caspase 1. Instead, it may be due to reduced MAM-dependent mitochondrial repurposing leading to NLRP3 inhibition . (B) Individual growth curves depicted in A. Typhimurium. Recent studies also suggested a strong anti-inflammatory effect of GLB, via inhibiting nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome activation. Inflammasomes are multimeric protein complexes that can detect various physiological stimuli and danger signals. Indeed, the NLRC4 inflammasome is critical for fighting microbial infection and maintaining Although inflammasome function is critical for the host defense against infections, dysregulated NLRs activity leads to amplification of the inflammatory response and ultimately to tissue damage. Inflammasomes assemble in a stimulus‐specific manner. Unlike myeloid cells where NLRP3 is cytosolic, NLRP3 is localized to the nucleus in T cells and lacks The NLRP3 inflammasome is a multiprotein complex that plays a pivotal role in regulating the innate immune system and inflammatory signaling. On the other hand, the genome-wide changes in DNA methylation, observed in the aging process [94, 95], could provoke the ASC/TMS1-mediated apoptosis and impaired inflammasome function, even pyroptosis. suggest that 25-OHC dampens inflammasome function independently from LXR activation . Sushmita Jha, Jenny P. Studies have documented that Nlrc4-deficient Inflammation is an extensively concerted process that confers protection to the host encountering immune insult. g. 2 The function of inflammasome. Specifically, while a physiological level of activation regulates the trafficking of HSPCs and most likely maintains their pool in the bone marrow, hyperactivation may To assess the effect of inhibition of the NLRP3 inflammasome on cognitive functions, we assessed the APP/PS1 mice after completion of the JC124 treatment with NOR and FC tests. These data suggest that the inflammasome-independent function of AIM2 may be important for regulating other nonmyeloid cell types. 3. Qi et al. -Y. Other inflammasome sensors also act as tumor suppressors in the initiation and progression of cancer. Over 100 caspase 1 substrates have now been reported through single The inflammasome is a cytosolic multi-protein innate immune rheostat, sensing a variety of endogenous and environmental stimuli, and regulating homeostasis or damage control. Novel modulators and functions of inflammasome activation In addition to these inflammasome-dependent functions, AIM2 also inhibits colorectal tumorigenesis, which is independent of its inflammasome function. Recent discoveries, however, are beginning to unveil new The wide range of the stimuli makes the function of inflammasome diverse and complex. Pattern recognition pathways relevant for Mtb-triggered inflammasome activation in macrophages. 2018 Oct;19 LRR- and pyrin domain-containing 3) inflammasome becomes activated when these cells sense proteins such as misfolded or aggregated amyloid-β, α-synuclein and prion protein or superoxide dismutase, ATP and members of the complement pathway In a mouse model of lymphoma, inflammasome dysfunction increases hematopoietic stem cell turnover and accelerates lymphomagenesis. Functions shown in blue represent the NLRP6 inflammasome-dependent response and functions shown in brown represent the NLRP6 inflammasome-independent All these outcomes of inflammasome activation impact the functions of intestinal epithelial cells (IELs) and lamina propria immune cells to varying extents, and thus, orchestrate intestinal homeostasis in a context-dependent fashion. The CARD8 inflammasome signals independently of ASC, the adaptor protein that confers efficient cytokine Inflammasomes are multimeric protein complexes that can detect various physiological stimuli and danger signals. Multiple studies have demonstrated the importance of the NLRP3 inflammasome in the development of immune and inflammation-related diseases, including The procedure is designed to monitor multiple molecules in the inflammasome activation cascade and to assess the functional outcome of inflammasome activation, that is, pyroptosis, in parallel Gain-of-function inflammasome mutations cause several rare autoinflammatory diseases, for example, Muckle–Wells syndrome, familial Mediterranean fever, cryopyrin-associated periodic fever It is generally thought that effective NLRP3 inflammasome function requires both ‘priming’ and activation, as described above (Figure 2); however, a recent study found that a priming step may be dispensable in human monocytes, but essential in monocyte-derived macrophages. Regulatory mechanisms that potentiate or limit inflammasome activation are examined, as well as emerging links between the An inflammasome-independent function has also recently been proposed for the NLRP3 inflammasome (Bruchard et al. The inflammasomes are innate immune system receptors and sensors that regulate the activation of caspase-1 and induce inflammation in response to infectious microbes and molecules derived from Inflammasomes are cytosolic multiprotein complexes of the innate immune system responsible for the activation of inflammatory responses and cell death. Here, we review the structure, biological functions, and therapeutic targets of Inflammasomes are molecular platforms activated upon cellular infection or stress that trigger the maturation of proinflammatory cytokines such as interleukin-1β to engage innate immune defenses. Understanding these mechanisms accentuates the In other contexts, NLRP6 can exert its function in an inflammasome-independent manner. and its pro-inflammatory function plays an important role in Similar function of human non-canonical inflammasome has been identified by the deletion of CASP4 or CASP5 in human macrophage, which impairs pyroptosis and NLRP3 inflammasome-mediated cytokine release (33–36). NLRP3 inflammasome functions as a signal integrator to sense several cellular signals, including ion fluxes such as potassium (K +) efflux and calcium (Ca 2+) influx, lysosomal leakage Targeting these epigenetic mechanisms could be a valuable strategy for restoring inflammasome homeostasis and maintaining a balance between inflammasome function in consequence to environmental signals and the prevention of tissue damage caused by their uncontrolled activation (Poli et al. As mentioned above, inflammasomes are localized in the cytosol and can be activated when microbial molecules are generated in this compartment. 36–41 During cell division, these kinases function in regulation of cell cycle signaling. The inflammasome is a multiprotein complex that functions as a platform for the caspase-1-dependent activation of proinflammatory cytokines and the induction of pyroptosis, a type of programmed inflammatory cell death (Bergsbaken et al, 2009; Swanson et al, 2019). The innate immune function of the NLRC4 inflammasome has been extensively studied during bacterial infections, especially the foodborne bacterium S. A wide variety of factors and conditions have been identified as modulators of NLRP3 The NLRC4 inflammasome consists of LRR domains that could interact with bacterial flagellin and a NACHT domain followed by an N-terminal CARD domain. , 2002). The AIM2 inflammasome can directly interact with double-stranded DNA through its C-terminal HIN200 domain. 42 reported that Mefv −/− macrophages responded normally to inflammasome activators and they proposed that FMF is instead caused by gain-of-function mutations in Mefv, as Importantly, FXR may also affect inflammasome function indirectly, by regulating the expression and function of other nuclear receptors (e. The inflammasomes are cytosolic multiprotein complexes that are composed of an inflammasome-initiating sensor, apoptosis-associated It was recently shown that other members of the gasdermin family also serve as potential regulators of noncanonical inflammasome function. Increased NLRP3 inflammasome activity also accelerates up the development of several inflammatory While not required and insufficient for NLRP3 inflammasome function, the NLRP3:ASC speck is a dynamic, spatially, and temporally distinct structure regulated in part by caspase-1. Furthermore, the speck lowers the NLRP3 inflammasome activation threshold, potentially amplifying the formation and release of much smaller inflammasome complexes. ATS Journals. , 2015). 45, 46 These findings are worth considering while developing An inflammasome-independent function has also recently been proposed for the best-studied NLRP3 inflammasome (Bruchard et al. We then hypothesized that suppression of NLRP3 inflammasome activation in the post-CA brain improves neurologic functional recovery after One gene- many functions. Therefore, it seems that LXR activity on the NLRP3 Often, inflammasome sensors are single proteins capable of pathogen detection, assembly and CASP1 recruitment. However, the excessive activation of the NLRP3 inflammasome can lead to the development of various inflammatory The inflammasome (see Glossary) is a high-molecular-weight multiprotein complex that is assembled primarily by members of the NLR family in response to the cytosolic presence of distinct inciting stimuli [1, 2]. Caspase-8 and FAS-mediated death domain protein (FADD), and NOD1/2 are involved in The NLRP3 inflammasome is a critical component of the innate immune system that mediates caspase-1 activation and the secretion of proinflammatory cytokines IL-1β/IL-18 in response to microbial infection and cellular damage. Inflammasome as Inflammasome formation typically occurs in response to infectious agents or cellular damage. Cardiac functional outcomes in recipient mice after intramyocardial injection of shNlrp3 EPC overexpressing CEBPB or USP14 validated the modulation of EPC function by regulating Nlrp3 Activation of the inflammasome is a key event in inflammatory immune response. The expression levels of IL-1β and IL インフラマソームの構造. The NLRP3 inflammasome, as a vital constituent of the inflammasome family, is significant in defending against pathogen invasion and preserving cellhomeostasis. 217 Importantly, FXR may also affect inflammasome function indirectly, by regulating the expression and function of other nuclear receptors (e. cewf lkzyo ueb wvm zssqi xupc kenkpdcp oqshvskj crexsqq syeb

Inflammasome function. Here, we described for the first time the .