Myeloid Protease-Activated Receptor-2 Contributes to Influenza A Virus Pathology in Mice.
Myeloid Protease-Activated Receptor-2 Contributes to Influenza A Virus Pathology in Mice.
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DOI：
10.3389/fimmu.2021.791017
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发表时间：
2021
影响因子：
7.3
通讯作者：
Antoniak S
中科院分区：
文献类型：
--
作者：
Gunther RC;Bharathi V;Miles SD;Tumey LR;Schmedes CM;Tatsumi K;Bridges MD;Martinez D;Montgomery SA;Beck MA;Camerer E;Mackman N;Antoniak S
对甲型流感病毒(IAV)感染的先天免疫反应部分由Toll样受体3(TLR3)启动。依赖于TLR3的信号诱导抗病毒免疫反应和依赖于核因子κB的炎症反应。蛋白水解酶激活受体2(PAR2)抑制抗病毒反应，增强炎症反应。PAR2缺乏对IAV感染小鼠具有保护作用。然而，PAR2表达的细胞类型在小鼠IAV病理中的作用以及PAR2促进IAV感染的机制尚不清楚。分析了全局(PAR2-/-)、髓系(PAR2fl/fl；LysMCre+)和肺上皮细胞(EPC)PAR2缺陷(Par2fl/fl；SPCCre+)小鼠及其各自对照(PAR2+/+和PAR2fl/fl)的IAV感染情况。此外，在骨髓来源的巨噬细胞(BMDM)中，分析了PAR2激活对TLR3多聚肌苷-多胞苷(Poly I：C)激活的影响。最后，我们测定了PAR2对野生型(WT)小鼠的抑制作用。在IAV感染后，与感染对照组相比，PAR2-/-和髓系PAR2缺陷小鼠的存活率增加。与感染对照组小鼠相比，PAR2-/-和PAR2 f1/fl；LysMCre+3天组小鼠的存活率提高与促炎介质减少和BALF中细胞浸润减少有关。有趣的是，与Par2fl/fl相比，PAR2fl/fl；SPCCre+小鼠没有显示出生存益处。体外研究表明，PAR2-/-BMDM在Poly I：C刺激后产生的IL6和IL12p40比PAR2+/+BMDM少。此外，在PAR2+/+BMDM上激活PAR2，与单独刺激PolyI：C相比，增加了PolyI：C对IL6和IL12p40的诱导。重要的是，在IAV感染之前抑制PAR2可以保护WT小鼠。全局性PAR2或髓系细胞而不是肺EPC PAR2缺陷与BALF炎症标志物减少和IAV诱导的死亡率降低相关。我们的研究表明，PAR2可能是减少IAV病理的治疗靶点。
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. IAV infection was analyzed in global (Par2-/- ), myeloid (Par2 fl/fl;LysMCre+) and lung epithelial cell (EpC) Par2 deficient (Par2fl/fl ;SPCCre+) 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. 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;LysMCre+ 3 days post infection (dpi) compared to infected control mice. Interestingly, Par2 fl/fl;SPCCre+ mice showed no survival benefit compared to Par2fl/fl . In vitro studies showed that Par2-/- BMDM produced less IL6 and IL12p40 than Par2 +/+ BMDM after poly I:C stimulation. In addition, activation of PAR2 on Par2 +/+ BMDM increased poly I:C induction of IL6 and IL12p40 compared to poly I:C stimulation alone. Importantly, PAR2 inhibition prior to IAV infection protect WT mice. Global Par2 or myeloid cell but not lung EpC Par2 deficiency was associated with reduced BALF inflammatory markers and reduced IAV-induced mortality. Our study suggests that PAR2 may be a therapeutic target to reduce IAV pathology.