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Skin Injury Activates a Rapid TRPV1-Dependent Antiviral Protein Response.

ABSTRACT: The skin serves as the interface between the body and the environment and plays a fundamental role in innate antimicrobial host immunity. Antiviral proteins (AVPs) are part of the innate host defense system and provide protection against viral pathogens. How breach of the skin barrier influences innate AVP production remains largely unknown. In this study, we characterized the induction and regulation of AVPs after skin injury and identified a key role of TRPV1 in this process. Transcriptional and phenotypic profiling of cutaneous wounds revealed that skin injury induces high levels of AVPs in both mice and humans. Remarkably, pharmacologic and genetic ablation of TRPV1-mediated nociception abrogated the induction of AVPs, including Oas2, Oasl2, and Isg15 after skin injury in mice. Conversely, stimulation of TRPV1 nociceptors was sufficient to induce AVP production involving the CD301b⁺ cells‒IL-27‒mediated signaling pathway. Using IL-27 receptor‒knockout mice, we show that IL-27 signaling is required in the induction of AVPs after skin injury. Finally, loss of TRPV1 signaling leads to increased viral infectivity of herpes simplex virus. Together, our data indicate that TRPV1 signaling ensures skin antiviral competence on wounding.

SUBMITTER: Lei V

PROVIDER: S-EPMC9259761 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Skin Injury Activates a Rapid TRPV1-Dependent Antiviral Protein Response.

Lei Vivian V Handfield Chelsea C Kwock Jeffery T JT Kirchner Stephen J SJ Lee Min Jin MJ Coates Margaret M Wang Kaiyuan K Han Qingjian Q Wang Zilong Z Powers Jennifer G JG Wolfe Sarah S Corcoran David L DL Fanelli Brian B Dadlani Manoj M Ji Ru-Rong RR Zhang Jennifer Y JY MacLeod Amanda S AS

The Journal of investigative dermatology 20220107 8

The skin serves as the interface between the body and the environment and plays a fundamental role in innate antimicrobial host immunity. Antiviral proteins (AVPs) are part of the innate host defense system and provide protection against viral pathogens. How breach of the skin barrier influences innate AVP production remains largely unknown. In this study, we characterized the induction and regulation of AVPs after skin injury and identified a key role of TRPV1 in this process. Transcriptional a ...[more]

PMID: 35007556

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Project description:UnlabelledMitochondrial dysfunction is a pathogenic feature of nonalcoholic steatohepatitis (NASH). NASH complicates hepatotropic viral disease. The mitochondrial antiviral signaling protein (MAVS) is the adapter of helicase receptors involved in sensing double-stranded RNA (dsRNA). We hypothesized that impaired MAVS function may contribute to insufficient antiviral response and liver damage in steatohepatitis. We identified reduced MAVS protein levels and increased MAVS association with the proteasome subunit alpha type 7 (PSMA7) in livers from mice given a methionine-choline-deficient (MCD) diet. Decreased association of MAVS with mitochondria and increased cytosolic cytochrome c indicated mitochondrial damage in steatohepatitis. In vivo administration of the synthetic dsRNA polyinosinic:polycytidylic acid [poly(I:C)], but not lipopolysaccharide or cytidine-phosphate-guanosine-rich DNA, resulted in impaired induction of type I interferons (IFNs) and proinflammatory cytokines in steatohepatitis. Consistent with a defect in helicase receptor-induced signaling, there was loss of poly(I:C)-induced translocation of MAVS to the cytosol and decreased IFN regulatory factor 3 phosphorylation. Caspases 1 and 8, both of which cleave MAVS, were increased in MCD diet-fed mice. At baseline, steatohepatitis was associated with increased serum alanine aminotransferase (ALT), apoptosis and caspase 3 activation compared with controls. In contrast to apoptosis in controls, necrosis was induced by poly(I:C) stimulation in steatohepatitis. Hepatocyte necrosis was indicated by elevated serum high-mobility group box protein-1 and ALT and was correlated with increased expression of receptor-interacting protein 3 (RIP3), a master regulator of necrosis. Increased expression of MAVS, PSMA7, and RIP3 messenger RNA was also present in human NASH livers.ConclusionOur novel findings suggest that mitochondrial damage in steatohepatitis extends to MAVS, an adapter of helicase receptors, resulting in inefficient type I IFN and inflammatory cytokine response but increased hepatocyte necrosis and RIP3 induction in response to a dsRNA viral challenge. These mechanisms may contribute to progressive liver damage and impaired viral clearance in NASH.

Dataset Information

Skin Injury Activates a Rapid TRPV1-Dependent Antiviral Protein Response.

Publications

Skin Injury Activates a Rapid TRPV1-Dependent Antiviral Protein Response.

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