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NLRP3 Inflammasome-A Key Player in Antiviral Responses.

ABSTRACT: The NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome is an oligomeric complex comprised of the NOD-like receptor NLRP3, the adaptor ASC, and caspase-1. This complex is crucial to the host's defense against microbes as it promotes IL-1? and IL-18 secretion and induces pyroptosis. NLRP3 recognizes variety of pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) generated during viral replication that triggers the NLRP3 inflammasome-dependent antiviral immune responses and facilitates viral eradication. Meanwhile, several viruses have evolved elaborate strategies to evade the immune system by targeting the NLRP3 inflammasome. In this review, we will focus on the crosstalk between the NLRP3 inflammasome and viruses, provide an overview of viral infection-induced NLRP3 inflammasome activation, and the immune escape strategies of viruses through their modulation of the NLRP3 inflammasome activity.

SUBMITTER: Zhao C

PROVIDER: S-EPMC7040071 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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NLRP3 Inflammasome-A Key Player in Antiviral Responses.

Zhao Chunyuan C Zhao Wei W

Frontiers in immunology 20200218

The NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome is an oligomeric complex comprised of the NOD-like receptor NLRP3, the adaptor ASC, and caspase-1. This complex is crucial to the host's defense against microbes as it promotes IL-1β and IL-18 secretion and induces pyroptosis. NLRP3 recognizes variety of pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) generated during viral replication that triggers the NLRP3 inflammasome-dep ...[more]

PMID: 32133002

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Project description:AimsObesity, an established risk factor of atrial fibrillation (AF), is frequently associated with enhanced inflammatory response. However, whether inflammatory signaling is causally linked to AF pathogenesis in obesity remains elusive. We recently demonstrated that the constitutive activation of the 'NACHT, LRR, and PYD Domains-containing Protein 3' (NLRP3) inflammasome promotes AF susceptibility. In this study, we hypothesized that the NLRP3 inflammasome is a key driver of obesity-induced AF.Methods and resultsWestern blotting was performed to determine the level of NLRP3 inflammasome activation in atrial tissues of obese patients, sheep, and diet-induced obese (DIO) mice. The increased body weight in patients, sheep, and mice was associated with enhanced NLRP3-inflammasome activation. To determine whether NLRP3 contributes to the obesity-induced atrial arrhythmogenesis, wild-type (WT) and NLRP3 homozygous knockout (NLRP3-/-) mice were subjected to high-fat-diet (HFD) or normal chow (NC) for 10 weeks. Relative to NC-fed WT mice, HFD-fed WT mice were more susceptible to pacing-induced AF with longer AF duration. In contrast, HFD-fed NLRP3-/- mice were resistant to pacing-induced AF. Optical mapping in DIO mice revealed an arrhythmogenic substrate characterized by abbreviated refractoriness and action potential duration (APD), two key determinants of reentry-promoting electrical remodeling. Upregulation of ultra-rapid delayed-rectifier K+-channel (Kv1.5) contributed to the shortening of atrial refractoriness. Increased profibrotic signaling and fibrosis along with abnormal Ca2+ release from sarcoplasmic reticulum (SR) accompanied atrial arrhythmogenesis in DIO mice. Conversely, genetic ablation of Nlrp3 (NLRP3-/-) in HFD-fed mice prevented the increases in Kv1.5 and the evolution of electrical remodeling, the upregulation of profibrotic genes, and abnormal SR Ca2+ release in DIO mice.ConclusionThese results demonstrate that the atrial NLRP3 inflammasome is a key driver of obesity-induced atrial arrhythmogenesis and establishes a mechanistic link between obesity-induced AF and NLRP3-inflammasome activation.

Dataset Information

NLRP3 Inflammasome-A Key Player in Antiviral Responses.

Publications

NLRP3 Inflammasome-A Key Player in Antiviral Responses.

Similar Datasets

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