The role of the anaphylatoxin C5a in intestinal immune responses

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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.