The NLRP3 inflammasome: molecular activation and regulation to therapeutics

By Karen V. Swanson, Meng Deng, J. Ting. Nature reviews. Immunology, 2019

4,091 citations recorded by the source corpus.

NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) is an intracellular sensor that detects a broad range of microbial motifs, endogenous danger signals and environmental irritants, resulting in the formation and activation of the NLRP3 inflammasome. Assembly of the NLRP3 inflammasome leads to caspase 1-dependent release of the pro-inflammatory cytokines IL-1β and IL-18, as well as to gasdermin D-mediated pyroptotic cell death. Recent studies have revealed new regulators of the NLRP3 inflammasome, including new interacting or regulatory proteins, metabolic pathways and a regulatory mitochondrial hub. In this Review, we present the molecular, cell biological and biochemical bases of NLRP3 activation and regulation and describe how this mechanistic understanding is leading to potential therapeutics that target the NLRP3 inflammasome. The NLRP3 inflammasome mediates pro-inflammatory responses and pyroptotic cell death. Here, the authors describe the complex pathways controlling its activation and regulation and how it is being targeted to treat inflammatory diseases.

Subfields: Molecular Biology, Public Health, Environmental and Occupational Health

View Paper: https://www.semanticscholar.org/paper/cb31e022a29129fe7d0a2a4e39436d25ad1adc8b

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In Molecular Biology

1. Jingjin Ding
2. Kun Wang
3. F. Shao
4. J. K. Kim
5. C. Sasakawa
6. E. Panieri
7. E. Jo
8. L. Saso

Citations in the corpus

• Gut Microbiota and Immune System Interactions (2020, background): “Moreover, SCFA-mediated GPR43 signaling attenuates NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome activation and subsequent secretion of IL-18, [20,21], a pro-inflammatory cytokine with essential roles in colonic inflammation and inflammation-associated cancers [11,22].”
• Structural Mechanism for GSDMD Targeting by Autoprocessed Caspases in Pyroptosis. (2020, background): “Excessive pyroptosis causes various inflammatory diseases like sepsis (Man et al., 2017; Manthiram et al., 2017; Swanson et al., 2019).”
• Update on the Pathomechanism, Diagnosis, and Treatment Options for Rheumatoid Arthritis (2020, background): “NLRP3 is an intracellular sensor belonging to the family of NOD-like receptors, which can form inflammasome complexes that regulate IL-1β secretion after detection of a wide array of danger signals [307].”
• An update on the regulatory mechanisms of NLRP3 inflammasome activation (2021, background): “During RNA virus infection, mitofusin 2 (MFN2) and mitochondrial antiviral signaling (MAVS) protein directly bind to and activate NLRP3.”
• An Overview of Nrf2 Signaling Pathway and Its Role in Inflammation (2020, background): “The pyrin domain containing 3 (NLRP3) inflammasome consists of an amino-terminal pyrin domain (PYD), a central NACHT domain and a carboxy-terminal leucine-rich repeat domain (LRR domain) [199].”
• Inflammation and atherosclerosis: signaling pathways and therapeutic intervention (2022, background): “However, some of the posttranslational modifications prevent NLRP3 inflammasome activation,(169) or stabilize the NLRP3 in a signal-competent but the autosuppressed state.(179) The ubiquitination of NLRP3 mediated by E3 ligases and deubiquitinating enzymes regulate NLRP3 stability.”