Dataset Information

Parkin Impairs Antiviral Immunity by Suppressing the Mitochondrial Reactive Oxygen Species-Nlrp3 Axis and Antiviral Inflammation.

ABSTRACT: Although mitochondria are known to be involved in host defense against viral infection, the physiological role of mitophagy, a crucial mechanism for maintaining mitochondrial homeostasis, in antiviral immunity remains poorly defined. Here, we show that Parkin, a central player in mitophagy, has a vital function in regulating host antiviral responses. Parkin-knockout mice exhibit improved viral clearance and survival after viral infection. However, Parkin deficiency does not affect antiviral signaling and interferon production. Instead, Parkin deficiency augments innate antiviral inflammation by enhancing mitochondrial ROS (mtROS)-mediated NLRP3 inflammasome activation and promoting viral clearance. Loss of NLRP3 can reverse the enhanced antiviral responses in Parkin knockout mice. Furthermore, we find that Parkin expression is downregulated in peripheral blood mononuclear cells of patients infected with virus. Collectively, our results suggest that Parkin plays an important role in antiviral immunity by controlling mtROS-NLRP3 axis-mediated inflammation. These findings provide physiological insight of the importance of mitophagy in regulating host antiviral response.

SUBMITTER: Li J

PROVIDER: S-EPMC6593176 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Parkin Impairs Antiviral Immunity by Suppressing the Mitochondrial Reactive Oxygen Species-Nlrp3 Axis and Antiviral Inflammation.

Li Jian J Ma Chunmei C Long Fei F Yang Dongxue D Liu Xue X Hu Yingchao Y Wu Chunyan C Wang Bingwei B Wang Min M Chen Yunzi Y Liu Genyan G Moynagh Paul N PN Zhou Jiawei J Peng Tao T Yang Shuo S

iScience 20190611

Although mitochondria are known to be involved in host defense against viral infection, the physiological role of mitophagy, a crucial mechanism for maintaining mitochondrial homeostasis, in antiviral immunity remains poorly defined. Here, we show that Parkin, a central player in mitophagy, has a vital function in regulating host antiviral responses. Parkin-knockout mice exhibit improved viral clearance and survival after viral infection. However, Parkin deficiency does not affect antiviral sign ...[more]

PMID: 31229895

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Project description:AimsIncreased fructose consumption predisposes the liver to nonalcoholic fatty liver disease (NAFLD), but the mechanisms are elusive. Thioredoxin-interacting protein (TXNIP) links oxidative stress to NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation and this signaling axis may be involved in fructose-induced NAFLD. Here, we explore the role of reactive oxygen species (ROS)-induced TXNIP overexpression in fructose-mediated hepatic NLRP3 inflammasome activation, inflammation, and lipid accumulation.ResultsRats were fed a 10% fructose diet for 8 weeks and treated with allopurinol and quercetin during the last 4 weeks. Five millimolars of fructose-exposed hepatocytes (primary rat hepatocytes, rat hepatic parenchymal cells [RHPCs], HLO2, HepG2) were co-incubated with antioxidants or caspase-1 inhibitor or subjected to TXNIP or NLRP3 siRNA interference. Fructose induced NLRP3 inflammasome activation and pro-inflammatory cytokine secretion, janus-activated kinase 2/signal transducers and activators of transcription 3-mediated inflammatory signaling, and expression alteration of lipid metabolism-related genes in cultured hepatocytes and rat livers. NLRP3 silencing and caspase-1 suppression blocked these effects in primary rat hepatocytes and RHPCs, confirming that inflammasome activation alters hepatocyte lipid metabolism. Hepatocellular ROS and TXNIP were increased in animal and cell models. TXNIP silencing blocked NLRP3 inflammasome activation, inflammation, and lipid metabolism perturbations but not ROS induction in fructose-exposed hepatocytes, whereas antioxidants addition abrogated TXNIP induction and diminished the detrimental effects in fructose-exposed hepatocytes and rat livers.Innovation and conclusionsThis study provides a novel mechanism for fructose-induced NAFLD pathogenesis by which the ROS-TXNIP pathway mediates hepatocellular NLRP3 inflammasome activation, inflammation and lipid accumulation. Antioxidant-based interventions can inhibit the ROS-TXNIP pathway.

Dataset Information

Parkin Impairs Antiviral Immunity by Suppressing the Mitochondrial Reactive Oxygen Species-Nlrp3 Axis and Antiviral Inflammation.

Publications

Parkin Impairs Antiviral Immunity by Suppressing the Mitochondrial Reactive Oxygen Species-Nlrp3 Axis and Antiviral Inflammation.

Similar Datasets

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