Negative regulators and their mechanisms in NLRP3 inflammasome activation and signaling

Kim, Jin‐Kyung; Jin, Hyo Sun; Suh, Hyun‐Woo; Jo, Eun-Kyeong

doi:10.1038/icb.2017.23

Cited by 41 publications

(27 citation statements)

References 73 publications

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“…Activation of D1 dopamine receptors on microglia increases intracellular cAMP levels, which as mentioned inhibits the NLRP3 and promotes its degradation via ubiquitination (Yan et al, 2015). Previous reviews have detailed the intracellular proteins and mechanisms that either prevent the formation or inhibit the activity of the NLRP3 inflammasome (Kim et al, 2017). …”

Section: Priming and Activation Of The Nlrp3 Inflammasomementioning

confidence: 99%

Principles of inflammasome priming and inhibition: Implications for psychiatric disorders

Herman

Pasinetti

2018

Brain, Behavior, and Immunity

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The production of inflammatory proteins by the innate immune system is a tightly orchestrated procedure that allows the body to efficiently respond to exogenous and endogenous threats. Recently, accumulating evidence has indicated that disturbances in the inflammatory response system not only provoke autoimmune disorders, but also can have deleterious effects on neuronal function and mental health. As inflammation in the brain is primarily mediated by microglia, there has been an expanding focus on the mechanisms through which these cells initiate and propagate neuroinflammation. Microglia can enter persistently active states upon their initial recognition of an environmental stressor and are thereafter prone to elicit amplified and persistent inflammatory responses following subsequent exposures to stressors. A recent focus on why primed microglia cells are susceptible to environmental insults has been the NLRP3 inflammasome. Its function within the innate immune system is regulated in such a manner that supports a role for the complex in gating neuroinflammatory responses. The activation of NLRP3 inflammasome in microglia results in the cleavage of zymogen inflammatory interleukins into functional forms that elicit a number of consequential effects in the local neuronal environment. There is evidence to support the principle that within primed neuroimmune systems a lowered threshold for NLRP3 activation can cause persistent neuroinflammation or the amplified production of inflammatory cytokines, such as IL-1β and IL-18. Over the course of an individual's lifetime, persistent neuroinflammation can subsequently lead to the pathophysiological signatures that define psychological disorders. Therefore, targeting the NLRP3 inflammasome complex may represent an innovative and consequential approach to limit neuroinflammatory states in psychiatric disorders, such as major depressive disorder.

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Section: Priming and Activation Of The Nlrp3 Inflammasomementioning

confidence: 99%

Principles of inflammasome priming and inhibition: Implications for psychiatric disorders

Herman

Pasinetti

2018

Brain, Behavior, and Immunity

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“…This response is driven by the assembly of an inflammasome, a multimolecular complex composed of an NLR and the adaptor protein apoptosis-associated speck-like protein (ASC), which recruits caspase-1. Caspase-1 activation in the complex leads to the proteolytic maturation of the pro-inflammatory cytokine interleukin 1β (IL-1β) and interleukin 18 (IL-18) ( 108 ). Recently, it has been shown that upon detection of mitochondrial ROS, and release of mitochondrial factors, NLRP3 relocates from the ER to the ER–mitochondria appositions, thus sensing the mitochondrial alteration and assembling the inflammasome ( 109 ).…”

Section: Fundamental Structural and Functional Roles Of The Mamsmentioning

confidence: 99%

Mitochondria-Associated Membranes As Networking Platforms and Regulators of Cancer Cell Fate

2017

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The tight cross talk between two essential organelles of the cell, the endoplasmic reticulum (ER) and mitochondria, is spatially and functionally regulated by specific microdomains known as the mitochondria-associated membranes (MAMs). MAMs are hot spots of Ca 2+ transfer between the ER and mitochondria, and emerging data indicate their vital role in the regulation of fundamental physiological processes, chief among them mitochondria bioenergetics, proteostasis, cell death, and autophagy. Moreover, and perhaps not surprisingly, it has become clear that signaling events regulated at the ER-mitochondria intersection regulate key processes in oncogenesis and in the response of cancer cells to therapeutics. ER-mitochondria appositions have been shown to dynamically recruit oncogenes and tumor suppressors, modulating their activity and protein complex formation, adapt the bioenergetic demand of cancer cells and to regulate cell death pathways and redox signaling in cancer cells. In this review, we discuss some emerging players of the ER-mitochondria contact sites in mammalian cells, the key processes they regulate and recent evidence highlighting the role of MAMs in shaping cell-autonomous and non-autonomous signals that regulate cancer growth.Keywords: endoplasmic reticulum, mitochondria, mitochondria-associated membranes, Ca 2+ signaling, eR stress, autophagy, inflammasome, cancer cell Abbreviations: AA, arachidonoyl; ATF4, activating transcription factor 4; ATG, autophagy-related gene; Bcl-2, B-cell lymphoma 2; Bcl-XL, B-cell lymphoma-extra large; BECN1, Beclin-1; Ca 2 + , calcium; Cav-1, caveolin-1; CL, cardiolipin; CNX, calnexin; cyt c, cytochrome c; Drp1, dynamin-related protein 1; ER, endoplasmic reticulum; Grp78, glucose-regulated protein 78; HK2, hexokinase 2; IL-1β, interleukin 1β; IL-18, interleukin 18; IP3, inositol trisphosphate; IP3R, inositol 1, 4, 5-trisphosphate receptor; IP3R3, inositol 1, 4, 5-trisphosphate receptor 3; IRE1, inositol requiring enzyme 1; MAMs, mitochondria-associated membranes; MAVS, mitochondrial antiviral-signaling protein; MCU, mitochondrial calcium uniporter; MFN2, mitofusin 2; mTORC2, mammalian target of rapamycin 2; NLRP3, NOD-like receptor family 3; OMM, outer mitochondrial membrane; ORP5, oxysterol-binding protein (OSBP)-related protein (ORP) 5; ORP8, oxysterol-binding protein (OSBP)-related protein (ORP) 8; PA, phosphatidic acid; PACS-2, phosphofurin acidic cluster sorting protein 2; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PERK, double stranded RNA-activated protein kinase (PKR)-like ER kinase; PI, phosphatidylinositol; PM, plasma membrane; PML, promyelocytic leukemia; PP2A, protein phosphatase 2A; PS, phosphatidylserine; PTEN, phosphatase and tensin homolog deleted on chromosome 10; PTPIP51, protein tyrosine phosphatase-interacting protein 51; ROS, reactive oxygen species; SERCA, sarco/endoplasmic reticulum Ca 2+ ATPase; SERCA2b, sarco/endoplasmic reticulum Ca 2 + ATPase isoform 2b; Sigma1 receptor, S1R; StAR, cholesterol transport steroidogenic acute regula...

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“…Among the NLRs, NLRP3 is best known for sensing the widest array of stimuli, such as nigericin, ATP, ROS, MSU and cholesterol . When the host receives a signal stimulus, NLRP3 itself can undergo oligomerization, increasing pro‐caspase‐1 through the adapter protein ASC, which activates caspase‐1 and then leads to the cleavage of the interleukin‐1β precursor (pro‐interleukin‐1β) and the interleukin‐18 precursor (pro‐interleukin‐18), causing corresponding inflammation factor IL‐1β and IL‐18 generation, thus inducing inflammation and necrosis (pyroptosis) and participating in the inflammatory response of cell and tissue …”

Section: Introductionmentioning

confidence: 99%

Gypenosides improve diabetic cardiomyopathy by inhibiting ROS‐mediated NLRP3 inflammasome activation

Zhang

Chen

Zong

et al. 2018

J Cellular Molecular Medi

107

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NLRP3 inflammasome activation plays an important role in diabetic cardiomyopathy (DCM), which may relate to excessive production of reactive oxygen species (ROS). Gypenosides (Gps), the major ingredients of Gynostemma pentaphylla (Thunb.) Makino, have exerted the properties of anti‐hyperglycaemia and anti‐inflammation, but whether Gps improve myocardial damage and the mechanism remains unclear. Here, we found that high glucose (HG) induced myocardial damage by activating the NLRP3 inflammasome and then promoting IL‐1β and IL‐18 secretion in H9C2 cells and NRVMs. Meanwhile, HG elevated the production of ROS, which was vital to NLRP3 inflammasome activation. Moreover, the ROS activated the NLRP3 inflammasome mainly by cytochrome c influx into the cytoplasm and binding to NLRP3. Inhibition of ROS and cytochrome c dramatically down‐regulated NLRP3 inflammasome activation and improved the cardiomyocyte damage induced by HG, which was also detected in cells treated by Gps. Furthermore, Gps also reduced the levels of the C‐reactive proteins (CRPs), IL‐1β and IL‐18, inhibited NLRP3 inflammasome activation and consequently improved myocardial damage in vivo. These findings provide a mechanism that ROS induced by HG activates the NLRP3 inflammasome by cytochrome c binding to NLRP3 and that Gps may be potential and effective drugs for DCM via the inhibition of ROS‐mediated NLRP3 inflammasome activation.

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Negative regulators and their mechanisms in NLRP3 inflammasome activation and signaling

Cited by 41 publications

References 73 publications

Principles of inflammasome priming and inhibition: Implications for psychiatric disorders

Principles of inflammasome priming and inhibition: Implications for psychiatric disorders

Mitochondria-Associated Membranes As Networking Platforms and Regulators of Cancer Cell Fate

Gypenosides improve diabetic cardiomyopathy by inhibiting ROS‐mediated NLRP3 inflammasome activation

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