Receptor interacting protein kinase 2-mediated mitophagy regulates inflammasome activation during virus infection
Christopher R. Lupfer,Paul G. Thomas,Paras K. Anand,Peter Vogel,Sandra Milasta,Jennifer Martinez,Gonghua Huang,Maggie Green,Mondira Kundu,Hongbo Chi,Ramnik J. Xavier,Ramnik J. Xavier,Douglas R. Green,Mohamed Lamkanfi,Mohamed Lamkanfi,Charles A. Dinarello,Peter C. Doherty,Peter C. Doherty,Thirumala-Devi Kanneganti +18 more
TLDR
A role for NOD2-RIPK2 signaling is demonstrated in protection against virally triggered immunopathology by negatively regulating activation of the NLRP3 inflammasome and production of IL-18 via ULK1-dependent mitophagy.Abstract:
NOD2 receptor and the cytosolic protein kinase RIPK2 regulate NF-κB and MAP kinase signaling during bacterial infections, but the role of this immune axis during viral infections has not been addressed. We demonstrate that Nod2(-/-) and Ripk2(-/-) mice are hypersusceptible to infection with influenza A virus. Ripk2(-/-) cells exhibited defective autophagy of mitochondria (mitophagy), leading to enhanced mitochondrial production of superoxide and accumulation of damaged mitochondria, which resulted in greater activation of the NLRP3 inflammasome and production of IL-18. RIPK2 regulated mitophagy in a kinase-dependent manner by phosphorylating the mitophagy inducer ULK1. Accordingly, Ulk1(-/-) cells exhibited enhanced mitochondrial production of superoxide and activation of caspase-1. These results demonstrate a role for NOD2-RIPK2 signaling in protection against virally triggered immunopathology by negatively regulating activation of the NLRP3 inflammasome and production of IL-18 via ULK1-dependent mitophagy.read more
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Autophagy in infection, inflammation and immunity
TL;DR: As discussed in this Review, autophagy has multitiered immunological functions that influence infection, inflammation and immunity.
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Targeting the NLRP3 inflammasome in inflammatory diseases
Matthew Mangan,Matthew Mangan,Edward James Olhava,William R. Roush,H. Martin Seidel,Gary D. Glick,Eicke Latz +6 more
TL;DR: Recent advances in the understanding of NLRP3 activation and regulation are reviewed, the evolving landscape ofNLRP3 modulators are highlighted and opportunities for pharmacologically targeting NL RP3 with novel small molecules are discussed.
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Regulation of inflammasome activation
TL;DR: Genetic studies indicate that mutations in NLRP1, NLRP3, NLRC4, and AIM2 are linked with the development of auto‐inflammatory diseases, enterocolitis, and cancer and transform the understanding of the basic biology and clinical relevance of inflammasomes.
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Inflammasome Complexes: Emerging Mechanisms and Effector Functions
TL;DR: Recent advances in understanding of the complex biology of the inflammasome are reviewed, with a focus on receptor components that regulate diverse biological processes, such as cellular proliferation, gene transcription, and tumorigenesis.
Journal ArticleDOI
Reactive oxygen species and mitochondria: A nexus of cellular homeostasis
TL;DR: The roles of mitochondria in the generation of ROS-derived anti-microbial effectors, the interplay of mitochondia and ROS with autophagy and the formation of DNA extracellular traps, and activation of the NLRP3 inflammasome by ROS and mitochondria are discussed.
References
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