The role of the anaphylatoxin C5a in intestinal immune responses

抗原提呈细胞（APC）在肠道黏膜免疫调节中发挥重要作用。它们是维持粘膜耐受性的组成部分，并驱动免疫反应以保护肠道免受病原体的侵害。肠道APC在耐受性和免疫调节中的双重作用的分子机制仍然难以捉摸。模式识别受体如APC上的Toll样受体被肠道细菌或病原体激活，通过平衡效应和调节性CD 4 T细胞应答来调节肠道免疫。肠道炎症通常导致补体激活和过敏毒素（AT）C3 a和C5 a的释放。我们的初步数据表明，AT受体表达在肠道APC上，但目前还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依赖性和非依赖性途径调节腹膜、肺和脾中的APC功能之外，我们的初步数据表明，C5 a抑制TLR 2驱动的IL-12从固有层（LP）DC产生，但增强IL-10从LP巨噬细胞产生。此外，我们发现LP CX 3CR 1+单核吞噬细胞在C5 aR-/-小鼠中减少。因此，我们提出，C5 aR受体和模式识别受体（PRRs）之间的串扰也发生在肠道APC调节先天性和适应性粘膜免疫反应。该建议旨在阐明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.