Myeloid Protease-Activated Receptor-2 Contributes to Influenza A Virus Pathology in Mice

作者：Randall Gunther, Vanthana Bharathi, Stephen Miles, Lauryn Tumey, Clare M. Schmedes, Kohei Tatsumi, Meagan D Bridges, David R. Martinez, Stephanie A. Montgomery, Melinda A. Beck, Eric Camerer, Nigel Mackman, Silvio Antoniak · 发表于：Frontiers in Immunology · 年份：2021 · DOI：10.3389/fimmu.2021.791017 · 被引用次数：9 · 研究领域：Blood Coagulation and Thrombosis Mechanisms、Immune Response and Inflammation、S100 Proteins and Annexins

Background Innate immune responses to influenza A virus (IAV) infection are initiated in part by toll-like receptor 3 (TLR3). TLR3-dependent signaling induces an antiviral immune response and an NFκB-dependent inflammatory response. Protease-activated receptor 2 (PAR2) inhibits the antiviral response and enhances the inflammatory response. PAR2 deficiency protected mice during IAV infection. However, the PAR2 expressing cell-types contributing to IAV pathology in mice and the mechanism by which PAR2 contributes to IAV infection is unknown. Methods IAV infection was analyzed in global ( Par2 -/- ), myeloid ( Par2 fl/fl ;LysM Cre+ ) and lung epithelial cell (EpC) Par2 deficient ( Par2 fl/fl ;SPC Cre+ ) mice and their respective controls ( Par2 +/+ and Par2 fl/fl ). In addition, the effect of PAR2 activation on polyinosinic-polycytidylic acid (poly I:C) activation of TLR3 was analyzed in bone marrow-derived macrophages (BMDM). Lastly, we determined the effect of PAR2 inhibition in wild-type (WT) mice. Results After IAV infection, Par2 -/- and mice with myeloid Par2 deficiency exhibited increased survival compared to infected controls. The improved survival was associated with reduced proinflammatory mediators and reduced cellular infiltration in bronchoalveolar lavage fluid (BALF) of Par2 -/- and Par2 fl/fl ;LysM Cre+ 3 days post infection (dpi) compared to infected control mice. Interestingly, Par2 fl/fl ;SPC Cre+ mice showed no survival benefit compared to Par2 fl/fl . In vitr...