C5aR1 and C5aR2 deficiency confer different degrees of protection against imiquimod-induced psoriasiform dermatitis

Psoriasis pathogenesis comprises both auto-immune and auto-inflammatory aspects. We hypothesized that complement anaphylatoxin C5a plays an important role in the pathogenesis of psoriasis via C5a receptor (C5aR) 1 and C5aR2 activation on neutrophils and through regulation of C5aR dependent IL-17/IL-23-mediated adaptive immune activation. The imiquimod (IMQ)-induced psoriasiform dermatitis mouse model was used. Wildtype (WT), C5ar1-/- and C5ar2-/- mice received a daily topical dose of IMQ cream on the shaved back for three or up to five consecutive days. Skin inflammation was assessed visually (modified mouse Psoriasis Area and Severity Index (PASI)), by histology, immunohistochemistry and gene expression of cytokines in the skin were measured by qPCR. Serum IL-17A was analyzed by ELISA. Compared to WT, C5ar1-/- mice demonstrated lower gene expression of IL-1β in the skin after three days and decreased influx of neutrophils, monocytes/macrophages, C9 deposition and circulating IL-17A after five days of IMQ treatment. Epidermal thickness and PASI-scores were significantly decreased in C5ar1-/- mice compared to WT at day five. C5ar2-/- mice showed mild protection on epidermal thickening after five days and demonstrated higher local IL-17F and systemic IL-17A responses after three days. This study shows a detrimental role for C5aR1 in the pathogenesis of psoriasiform dermatitis in mice and confirms the link between C5a-C5aR1, IL-1β and IL-17A. C5ar2-/- mice showed only modest protection against IMQ-induced psoriasiform dermatitis. Therefore, inhibition of the C5a-C5aR1 axis might be a promising novel approach in the treatment of psoriasis.