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The role of the anaphylatoxin C5a in intestinal immune responses

过敏毒素 C5a 在肠道免疫反应中的作用

基本信息

批准号：
213879527
负责人：
Professor Dr. Jörg Köhl
金额：
--
依托单位：
Institut für Systemische Entzündungsforschung (ISEF)
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2012
资助国家：
德国
起止时间：
2011-12-31 至 2014-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/213879527?language=en
关键词：
role anaphylatoxin C5a intestinal immune

项目摘要

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.

抗原呈递细胞（APC）在肠道粘膜免疫的调节中发挥关键作用。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至关重要。肠道 APC 在耐受性和免疫调节中的双重作用背后的分子机制仍然难以捉摸。共生细菌或病原体激活模式识别受体（例如 APC 上的 Toll 样受体），通过平衡效应细胞和调节性 CD4 T 细胞反应来调节肠道免疫。肠道炎症通常会导致补体激活并释放过敏毒素 (AT) C3a 和 C5a。我们的初步数据显示AT受体在肠道APC上表达；但尚不清楚这种表达是否会因肠道炎症而受到调节。除了通过 TLR 依赖性和独立途径调节腹膜、肺和脾中的 APC 功能外，我们的初步数据表明，C5a 抑制固有层 (LP) DC 中 TLR2 驱动的 IL-12 产生，但增强 LP 巨噬细胞产生 IL-10。此外，我们发现 C5aR-/- 小鼠中 LP CX3CR1+ 单核吞噬细胞减少。因此，我们认为 C5aR 受体和模式识别受体 (PRR) 之间的串扰也发生在调节先天性和适应性粘膜免疫反应的肠道 APC 中。该提案旨在描述这种串扰背后的分子机制、其对粘膜耐受性和炎症性肠病发展的影响。