Essential Roles of CCL2-CCR2 and C5a-C5aR1 Pathways in irritant Contact Dermatitis

Abstract Cutaneous immune response induced by epithelial cell stress induces represents the first line defense against pathogens. We have reported that basophils play a pivotal role in the skin inflammation caused by irritants. However, it has not been fully understood how they accumulate in the skin. Previous studies have shown that epithelial cell damage induces complement activation in organs such as the lung and the kidney, implicating a possible involvement of the complement activation in the immune response caused by epithelial cell stress in the skin. Thus, we investigated the mechanism of basophil recruitment to the skin focusing on the complement system. Topical application of the surfactant sodium dodecyl sulfate (SDS) onto murine ears induced basophil-dependent skin inflammation. Among chemokines which were up-regulated by SDS application, we found that CCL2-CCR2 axis was critical for basophil recruitment to the skin. Here, CCR2 on basophils was dispensable and CCR2 on radioresistant cells was essential. Finally, we evaluated the contribution of complement system to SDS-induced basophil recruitment to the skin. SDS application induced C3 and C5a production in the skin, suggesting a complement activation in the skin. We evaluated whether C3 and C5a are involved in SDS-induced basophil recruitment by using C3 deficient mice and C5a receptor 1 deficient mice. The result showed that C3 deficiency or C5aR1 deficiency significantly attenuated SDS-induced basophils accumulation. By contrast, SDS-induced CCL2 production in these mice was comparable to WT mice. Collectively, our data suggest that both CCL2-CCR2 and C5a-C5aR pathways are essential to the SDS-induced innate immune response in the skin by modulating basophil recruitment.