Abstract：
Emerging evidence suggests that signaling through the C3a anaphylatoxin receptor (C3aR) protects against various inflammation-related diseases. However, the role of C3aR in psoriasis remains unknown. The purpose of this study was to investigate the possible protective role of C3aR in psoriasis and to explore the underlying molecular mechanisms. We initially found that the psoriatic epidermis exhibited significantly decreased C3aR expression. C3aR showed protective roles in mouse models of imiquimod (IMQ)- and interleukin-23-induced psoriasis. Furthermore, increased epidermal thickness and keratin 6 (K6), K16, and K17 expression occurred in the ears and backs of C3aR-/- mice. Pharmacological treatment with a C3aR agonist ameliorated IMQ-induced psoriasiform lesions in mice and decreased the expression of K6, K16, and K17. Additionally, the signal transducer and activator of transcription 3 (STAT3) pathway participated in the protective function of C3aR. More importantly, the expression levels of K6, K16, and K17 in keratinocytes were all restored in HaCaT cells transfected with a C3aR-overexpression plasmid after treating them with colivelin (a STAT3 activator). Our findings demonstrate that C3aR protects against the development of psoriasis and suggest that C3aR confers protection by negatively regulating K6, K16, and K17 expression in a STAT3-dependent manner, thus inhibiting keratinocyte proliferation and helping reverse the pathogenesis of psoriasis.
摘要：
新出现的证据表明，通过C3a过敏毒素受体（C3aR）的信号传导可以预防各种炎症相关疾病。然而,C3aR在银屑病中的作用尚不清楚.目的探讨C3aR在银屑病中可能的保护作用，并探讨其潜在的分子机制。我们最初发现银屑病表皮表现出显著降低的C3aR表达。C3aR在咪喹莫特（IMQ）和白介素23诱导的牛皮癣的小鼠模型中显示出保护作用。此外，表皮厚度和角蛋白6（K6）增加，K16和K17表达出现在C3aR-/-小鼠的耳朵和背部。C3aR激动剂的药物治疗改善了IMQ诱导的小鼠银屑病样病变，并降低了K6，K16和K17的表达。此外,信号转导和转录激活因子3(STAT3)通路参与了C3aR的保护功能。更重要的是,在用Colivelin(一种STAT3激活剂)处理后,用C3aR过表达质粒转染的HaCaT细胞中,K6,K16和K17的表达水平均得到恢复.我们的发现表明，C3aR可以防止银屑病的发展，并表明C3aR通过以STAT3依赖性方式负调节K6，K16和K17表达来赋予保护作用。从而抑制角质形成细胞增殖，帮助逆转银屑病的发病机制。
