Recent insights into the regulatory networks of NLRP3 inflammasome activation DOI Open Access
Alexander N.R. Weber, Zsofia Bittner, Sangeetha Shankar

et al.

Journal of Cell Science, Journal Year: 2020, Volume and Issue: 133(23)

Published: Dec. 1, 2020

The NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome is a fascinating cellular machinery endowed with the capacity for rapid proteolytic processing of pro-inflammatory cytokine IL-1β cell death effector gasdermin D (GSDMD). Although its activity essential to fight infection support tissue homeostasis, complex, which consists danger sensor NLRP3, adaptor apoptosis-associated speck-like containing CARD (ASC; also known as PYCARD), caspase-1 probably other regulatory proteins, bears considerable potential detrimental inflammation, observed in human conditions such gout, heart attack, stroke Alzheimer's disease. Thus, multi-layered networks are required ensure fine balance between responsiveness versus erroneous activation (sufficient temporally restricted excessive chronic activity) inflammasome. These involve multiple activation, secretion pathways, well modulation subcellular localization structure activity, owing post-translational modification by proteins. Here, we discuss exciting progress that has recently been made deciphering regulation NLRP3 Additionally, highlight open questions describe areas research warrant further exploration obtain more comprehensive molecular understanding

Language: Английский

The NLRP3 inflammasome: molecular activation and regulation to therapeutics DOI
Karen V. Swanson, Meng Deng, Jenny P.‐Y. Ting

et al.

Nature reviews. Immunology, Journal Year: 2019, Volume and Issue: 19(8), P. 477 - 489

Published: April 29, 2019

Language: Английский

Citations

3561
The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and Regulation DOI Open Access
Nathan Kelley, Devon Jeltema, Yanhui Duan

et al.

International Journal of Molecular Sciences, Journal Year: 2019, Volume and Issue: 20(13), P. 3328 - 3328

Published: July 6, 2019

The NLRP3 inflammasome is a critical component of the innate immune system that mediates caspase-1 activation and secretion proinflammatory cytokines IL-1β/IL-18 in response to microbial infection cellular damage. However, aberrant has been linked with several inflammatory disorders, which include cryopyrin-associated periodic syndromes, Alzheimer’s disease, diabetes, atherosclerosis. activated by diverse stimuli, multiple molecular events, including ionic flux, mitochondrial dysfunction, production reactive oxygen species, lysosomal damage have shown trigger its activation. How responds those signaling events initiates assembly not fully understood. In this review, we summarize our current understanding mechanisms regulation post-translational modifications interacting partners NLRP3.

Language: Английский

Citations

2726
Recent advances in the mechanisms of NLRP3 inflammasome activation and its inhibitors DOI Creative Commons
Yang Yang, Huanan Wang,

Mohammed Kouadir

et al.

Cell Death and Disease, Journal Year: 2019, Volume and Issue: 10(2)

Published: Feb. 12, 2019

Abstract The NLRP3 inflammasome is a multimeric protein complex that initiates an inflammatory form of cell death and triggers the release proinflammatory cytokines IL-1β IL-18. has been implicated in wide range diseases, including Alzheimer’s disease, Prion type 2 diabetes, some infectious diseases. It found variety stimuli danger-associated molecular patterns (DAMPs, such as silica uric acid crystals) pathogen-associated (PAMPs) can activate inflammasome, but specific regulatory mechanisms activation remain unclear. Understanding will enable development its inhibitors to treat NLRP3-related In this review, we summarize current understanding well specifically directly target NLRP3.

Language: Английский

Citations

1067
An update on the regulatory mechanisms of NLRP3 inflammasome activation DOI Creative Commons
Seungwha Paik, Jin Kyung Kim, Prashanta Silwal

et al.

Cellular and Molecular Immunology, Journal Year: 2021, Volume and Issue: 18(5), P. 1141 - 1160

Published: April 13, 2021

Abstract The NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome is a multiprotein complex involved in the release of mature interleukin-1β triggering pyroptosis, which paramount importance variety physiological pathological conditions. Over past decade, considerable advances have been made elucidating molecular mechanisms underlying priming/licensing (Signal 1) assembly 2) NLRP3 activation. Recently, number studies indicated that step regulated by complicated at both transcriptional posttranslational levels. In this review, we discuss current understanding mechanistic details activation with particular emphasis on protein-protein interactions, modifications, spatiotemporal regulation machinery. We also present detailed summary multiple positive and/or negative regulatory pathways providing upstream signals culminate assembly. A better will provide opportunities for development methods prevention treatment inflammasome-related diseases.

Language: Английский

Citations

539
Structural Mechanisms of NLRP3 Inflammasome Assembly and Activation DOI Creative Commons
Jianing Fu, Hao Wu

Annual Review of Immunology, Journal Year: 2023, Volume and Issue: 41(1), P. 301 - 316

Published: Feb. 8, 2023

As an important sensor in the innate immune system, NLRP3 detects exogenous pathogenic invasions and endogenous cellular damage responds by forming inflammasome, a supramolecular complex that activates caspase-1. The three major components of inflammasome are NLRP3, which captures danger signals recruits downstream molecules; caspase-1, elicits maturation cytokines IL-1β IL-18 processing gasdermin D to mediate cytokine release pyroptosis; ASC (apoptosis-associated speck-like protein containing caspase recruitment domain), functions as bridge connecting In this article, we review structural information has been obtained on its or subcomplexes, with special focus inactive cage, active NLRP3-NEK7 (NIMA-related kinase 7)-ASC disk, PYD-PYD CARD-CARD homotypic filamentous scaffolds inflammasome. We further implicate structure-derived mechanisms for assembly activation

Language: Английский

Citations

529
The NLRP3 inflammasome: activation and regulation DOI Creative Commons
Jie Xu, Gabriel Núñez

Trends in Biochemical Sciences, Journal Year: 2022, Volume and Issue: 48(4), P. 331 - 344

Published: Nov. 4, 2022

Language: Английский

Citations

290
Metformin protects against myocardial ischemia-reperfusion injury and cell pyroptosis via AMPK/NLRP3 inflammasome pathway DOI Creative Commons
Jing Zhang,

Lelin Huang,

Xingming Shi

et al.

Aging, Journal Year: 2020, Volume and Issue: 12(23), P. 24270 - 24287

Published: Nov. 21, 2020

Ischemia/reperfusion (I/R) injury is a life-threatening vascular emergency following myocardial infarction. Our previous study showed cardioprotective effects of metformin against I/R injury. In this study, we further examined the involvement AMPK mediated activation NLRP3 inflammasome in effect metformin. Myocardial was simulated rat heart Langendorff model and neonatal ventricle myocytes (NRVMs) were subjected to hypoxi/reoxygenation (H/R) establish an vitro model. Outcome measures included infarct size, hemodynamic monitoring, tissue injury, apoptotic index inflammatory response. size cardiac enzyme activities. First, found that postconditioning can not only significantly alleviated attenuated cell apoptosis, inhibited fibrosis. Furthermore, activated phosphorylated AMPK, decreased pro-inflammatory cytokines, TNF-α, IL-6 IL-1β, activation. isolated NRVMs increased cellular viability, LDH activity apoptosis inflammation. Importantly, inhibition phosphorylation by Compound C (CC) resulted survival cardiomyocytes mainly inducing release cytokines increasing Finally, studies revealed activator nigericin abolished anti-inflammatory NRVMs, but it had little on phosphorylation. Collectively, our confirmed exerts regulating injury-induced response, which largely dependent enhancement pathway, thereby suppressing

Language: Английский

Citations

209
Structure of the NLRP3 decamer bound to the cytokine release inhibitor CRID3 DOI
Inga V. Hochheiser, Michael Pilsl, Gregor Hagelueken

et al.

Nature, Journal Year: 2022, Volume and Issue: 604(7904), P. 184 - 189

Published: Feb. 3, 2022

Language: Английский

Citations

200
The NLRP3 inflammasome in traumatic brain injury: potential as a biomarker and therapeutic target DOI Creative Commons
William T. O’Brien,

Louise Pham,

Georgia F. Symons

et al.

Journal of Neuroinflammation, Journal Year: 2020, Volume and Issue: 17(1)

Published: April 6, 2020

There is a great clinical need to identify the underlying mechanisms, as well related biomarkers, and treatment targets, for traumatic brain injury (TBI). Neuroinflammation central pathophysiological feature of TBI. NLRP3 inflammasome activity necessary component innate immune response tissue damage, dysregulated has been implicated in number neurological conditions. This paper introduces its implication pathogenesis neuroinflammatory-related conditions, with particular focus on Although role TBI only recently identified, findings suggest that priming activation are upregulated following Moreover, recent studies utilizing specific inhibitors have provided further evidence this major driver neuroinflammation neurobehavioral disturbances In addition, there emerging circulating inflammasome-associated proteins may utility diagnostic biomarkers neuroinflammatory including Finally, novel promising areas research will be highlighted, potential involvement mild TBI, how factors such biological sex affect use biomarker platforms. Taken together, review highlights exciting target treatments ultimately used improve management.

Language: Английский

Citations

175
How location and cellular signaling combine to activate the NLRP3 inflammasome DOI Creative Commons

Anil Akbal,

Alesja Dernst,

Marta Lovotti

et al.

Cellular and Molecular Immunology, Journal Year: 2022, Volume and Issue: 19(11), P. 1201 - 1214

Published: Sept. 20, 2022

Abstract NOD-, LRR-, and pyrin domain-containing 3 (NLRP3) is a cytosolic innate immune sensor of cellular stress signals, triggered by infection sterile inflammation. Upon detection an activating stimulus, NLRP3 transitions from inactive homo-oligomeric multimer into active multimeric inflammasome, which promotes the helical oligomeric assembly adaptor molecule ASC. ASC oligomers provide platform for caspase-1 activation, leading to proteolytic cleavage activation proinflammatory cytokines in IL-1 family gasdermin D, can induce lytic form cell death. Recent studies investigating both requirement structure have revealed complex regulation multiple steps involved its activation. This review presents perspective on biochemical processes controlling inflammasome with particular emphasis structural role organelles. We also highlight latest research metabolic control this inflammatory pathway discuss promising clinical targets intervention.

Language: Английский

Citations

133