Initiation and perpetuation of NLRP3 inflammasome activation and assembly

By Eric I. Elliott, F. Sutterwala. Immunological Reviews, 2015

780 citations recorded by the source corpus.

The NLRP3 (NOD‐like receptor family, pyrin domain containing 3) inflammasome is a multiprotein complex that orchestrates innate immune responses to infection and cell stress through activation of caspase‐1 and maturation of inflammatory cytokines pro‐interleukin‐1β (pro‐IL‐1β) and pro‐IL‐18. Activation of the inflammasome during infection can be protective, but unregulated NLRP3 inflammasome activation in response to non‐pathogenic endogenous or exogenous stimuli can lead to unintended pathology. NLRP3 associates with mitochondria and mitochondrial molecules, and activation of the NLRP3 inflammasome in response to diverse stimuli requires cation flux, mitochondrial Ca2+ uptake, and mitochondrial reactive oxygen species accumulation. It remains uncertain whether NLRP3 surveys mitochondrial integrity and senses mitochondrial damage, or whether mitochondria simply serve as a physical platform for inflammasome assembly. The structure of the active, caspase‐1‐processing NLRP3 inflammasome also requires further clarification, but recent studies describing the prion‐like properties of ASC have advanced the understanding of how inflammasome assembly and caspase‐1 activation occur while raising new questions regarding the propagation and resolution of NLRP3 inflammasome activation. Here, we review the mechanisms and pathways regulating NLRP3 inflammasome activation, discuss emerging concepts in NLRP3 complex organization, and expose the knowledge gaps hindering a comprehensive understanding of NLRP3 activation.

Subfields: Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/011a694da2591d337aa19fdc6d05f1547e987d83

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In Immunology

1. G. Núñez
2. H. Hara
3. Yuan He

In Molecular Biology

1. Yuan He
2. H. Hara
3. G. Núñez

Citations in the corpus

• Reactive oxygen species and mitochondria: A nexus of cellular homeostasis (2015, background): “Activation of the NLRP3 inflammasome has been covered in great detail elsewhere [11,84,117–119].”
• Pyroptosis in inflammatory diseases and cancer (2022, background): “The NLRP3 is activated by various factors, including bacteria, viruses, fungi, uric acid, reactive oxygen species (ROS), adenosine triphosphoric (ATP), and endogenous damage signals [28].”
• Mechanism and regulation of NLRP3 inflammasome activation (2016, background): “Mitochondrial Dysfunction and ROS The role of ROS and the mitochondria in NLRP3 inflammasome activation is a topic of longstanding debate [43,44].”
• Role of pyroptosis in inflammation and cancer (2022, background): “Endogenous danger signals, such as pore-forming toxins, crystalline structures, and extracellular ATP or RNA, can trigger activation of the NLRP3 inflammasome, which decreases the intracellular K concentration, promotes the release of cellular lysate from lysosomes, and induces mitochondrial damage ”