Role of signal transduction pathway in host defense during sepsis

STAT通路介导的细胞因子信号受SOCS蛋白的负调控。在本项目中，我们研究了抑制STAT3/4/6通路的SOCS3/5在脓毒症期间先天免疫中的作用。在T细胞中细胞特异性过表达SOCS5的小鼠（SOCS5Tg）相对于野生型（WT）小鼠具有抗致死性。这是由于SOCS5Tg小鼠先天免疫增强，其中过表达SOCS5的CD4+T细胞增强了中性粒细胞和巨噬细胞的1型免疫反应。在缺乏趋化因子受体8 （CCR8）的小鼠中，败血症期间的1型反应也增强，这表明趋化因子信号在先天免疫中起重要作用。在炎症中，常驻巨噬细胞，而不是其他类型的细胞，通过Stat3信号通路介导IL-10的抗炎作用，发挥调节作用。缺乏STAT3的巨噬细胞Fcy受体和补体受体1 （CCR1）的表达降低，而缺乏SOCS3的巨噬细胞则相反。这可能是缺乏STAT3/SOCS3的巨噬细胞吞噬活性增强的原因。吞噬细胞中细胞特异性缺失STAT3的小鼠增强了Thl和Th2型获得性免疫应答，可能是由于细胞外APC活性增强。另一方面，在T细胞中细胞特异性过表达SOCS3的小鼠（SOCS3Tg小鼠）由于组织中1型反应降低而对脓毒症具有抵抗力，从而减轻了器官损伤。SOCS3Tg小鼠还通过增加肝细胞中STAT1的激活而降低STAT3的激活而对药物诱导的肝毒性有害。

Cytokine signaling mediated by STAT pathway is negatively regulated by SOCS proteins. In this project, we have investigated the role of SOCS3/5 that inhibit STAT3/4/6 pathway, in innate immunity during sepsis. Mice with a cell-specific overexpression of SOCS5 in T cells (SOCS5Tg) were resistant to the lethality relative to the wild-type (WT) mice. This was due to the enhanced innate immunity in SOCS5Tg mice whereby CD4+T cells with overexpressed SOCS5 augment type-1 immune response of neutrophils and macrophages. Enhanced type-1 response during sepsis was also seen in mice lacking chemokine receptor 8 (CCR8), suggesting an important role of chemokine signaling in innate immunity. In inflammation, resident macrophages, but not other cell types, play a regulatory role through a Stat3 signaling pathway by mediating the anti-inflammatory role of IL-10. Macrophages lacking STAT3 showed decreased expression of Fcy receptor and compliment receptor 1 (CCR1), which was conversely augmented in macrophages lacking SOCS3. This might be responsible for the augmented phagocytic activities of macrophages lacking STAT3/SOCS3. Mice with a cell-specific deletion of STAT3 in phagocytes augmented Thl and Th2 type acquired immune response, possibly due to enhanced APC activities off the cells. On the other hand, mice with a cell-specific overexpression of SOCS3 in T cells (SOCS3Tg mice) were resistant to sepsis due to decreased type-1 response in tissue, resulting in alleviated organ damage. The SOCS3Tg mice were also deleterious in drug-induced hepatotoxicity by increasing STAT1 activation while decreasing STAT3 activation in hepatocytes.