Abstract: Objective To explore the effects and underlying mechanism of C5a/C5aR1 pathway in mediating imiquimod (IMQ)-induced psoriatic skin inflammation by increasing IL-17A expression in γδ T cells. Methods C5aR1^+/+ and C5aR1^-/- mice were treated with IMQ or control Vasline cream for 6 consecutive days. The psoriatic skin inflammation was monitored. Inflammatory cells infiltration (T cells and neutrophils) and cytokines expression (IL-17A and TNF-α) were tested by immunohistochemistry (IHC). The percentages and cellular sources of IL-17A in both draining lymph nodes and skin lesions were analyzed by flow cytometry (FCM). Before IMQ application,C5aR1a peptide was injected into C5aR1^+/+ mice and the psoriatic skin lesions as well as IL-17A expression were examined. Additionally, the isolated spleen lymphocytes were stimulated with C5a, IL23 or C5aR1a and then tested with FCM for the expression of IL-17A in γδ T cells. Results It was shown that C5aR1 deficiency clearly ameliorated IMQ induced psoriatic skin inflammation and was coupled with decreased keratinocytes proliferation, attenuated CD3 positive T cells and neutrophils, alleviated cytokines expression (IL-17A and TNF-α). FCM results indicated that C5aR1 loss significantly decreased the percentages of IL-17A positive cells in both draining lymph nodes and skin lesions, and γδ CD3⁺ TCR⁺ T cell was proved to be the major source of IL-17A. In consistent with that, blocking C5a/C5aR1 pathway with C5aR1a peptide remarkably alleviated IMQ induced skin lesions and IL-17A responses. Moreover, blocking C5a/C5aR1 with C5aR1a significantly down-regulated IL-17A expression in γδ T cells in vitro. Conclusions This study indicates that C5a/C5aR1 signaling plays an essential role in the pathogenesis of psoriatic lesions by enhancing IL-17A expression by γδ T cells. Blocking C5a/C5aR1 pathway is a promise strategy in the treatment of psoriasis patients.

Key words: psoriasis, C5a/C5aR1 pathway, interleukin-17A(IL-17A), γδ T cells