The role of the anaphylatoxin C5a in intestinal immune responses

抗原呈递细胞（APCs）在肠粘膜免疫的调控中发挥关键作用。它们对于维持粘膜耐受性和驱动免疫反应以保护肠道免受病原体侵害是不可或缺的。肠道APCs在调节耐受性和免疫中的双重作用的分子机制尚不清楚。共生菌或病原体激活apc上的toll样受体等模式识别受体，通过平衡效应和调节性CD4 T细胞反应来调节肠道免疫。肠道炎症常导致补体活化和过敏毒素（ATs） C3a和C5a的释放。我们的初步数据显示AT受体在肠道apc上表达；然而，尚不清楚这种表达是否在肠道炎症反应中被调节。除了通过tlr依赖和独立途径调节腹膜、肺和脾脏的APC功能外，我们的初步数据表明，C5a抑制tlr2驱动的固有层（LP） dc产生IL-12，但增强LP巨噬细胞产生IL-10。此外，我们发现LP CX3CR1+单核吞噬细胞在C5aR-/-小鼠中减少。因此，我们认为C5aR受体和模式识别受体（PRRs）之间的串音也发生在调节先天性和适应性粘膜免疫反应的肠道apc中。本提案旨在描述这种串扰的分子机制，其对粘膜耐受性和炎症性肠病发展的影响。

Antigen presenting cells (APCs) exert key roles in the regulation of mucosal immunity of the intestine. They are integral for the maintenance of mucosal tolerance and drive immune responses to protect the intestine from pathogens. The molecular mechanisms underlying this dual role of intestinal APCs in the regulation of tolerance and immunity remain elusive. Activation of pattern recognition receptors such as the Toll-like receptors on APCs by commensal bacteria or by pathogens regulates intestinal immunity by balancing effector and regulatory CD4 T cell responses. Intestinal inflammation often results in complement activation and release of the anaphylatoxins (ATs) C3a and C5a. Our preliminary data show that AT receptors are expressed on intestinal APCs; yet it is unclear whether such expression is modulated in response to intestinal inflammation. In addition to regulation of APC functions in peritoneum, lung and spleen by TLR-dependent and independent pathways our preliminary data suggest that C5a suppresses TLR2-driven IL-12 production from lamina propria (LP) DCs but enhances IL-10 production from LP macrophages. Further, we found that LP CX3CR1+ mononuclear phagocytes were reduced in C5aR-/- mice. Thus, we propose that cross-talk between C5aR receptors and pattern recognition receptor (PRRs) also occurs in intestinal APCs regulating innate and adaptive mucosal immune responses. This proposal aims at delineating the molecular mechanisms underlying such crosstalk, its impact on mucosal tolerance and the development of inflammatory bowel disease.