C5aR and TLR crosstalk Regulatory effect of anaphylatoxin C5a on human dendritic cells

Dendritic cells (DCs) and the complement system are two essential parts of our immune system, that are both involved in pathogen recognition and elimination. Increased levels of both DCs and complement activation products are observed during infection and in several autoimmune diseases, indicating that crosstalk between these two arms of innate immunity is likely to occur. Until recently, however, data on the interplay between complement and DC activation, especially in humans, is limited. The potential use of complement interfering compounds for treatment of several diseases, emphasizing the importance of understanding the effect of complement on DC activation. In this thesis, we aim to clarify the effect of C5aR and TLR crosstalk on the activation of human DCs. C5a reduced the production of TLR-induced pro-inflammatory cytokines by DCs. IL-10 induction upon accelerated TLR-induced ERK/p38-CREB1 signaling was demonstrated to be key in the regulatory effect of C5a on pro-inflammatory cytokine production. In line with these findings, C5a-priming of DCs reduced T cell responses. RNA sequencing analyses demonstrated that C5aR and TLR crosstalk in addition induces a core regulatory network in DCs. In the absence of a TLR stimulus, C5a specifically inhibited Fc-gamma receptor mediated uptake of immune complexes. Overall, we discovered a potential regulatory role of C5a in human DC activation, which may especially be of importance to prevent the development of autoimmunity and to regulate inflammation during bacterial infections. The use of C5/C5a interfering drugs should, therefore, be considered with extreme care.