ABSTRACT
@#[摘 要] C5AR1是补体激活片段C5a的受体，主要在粒细胞、单核细胞、树突状细胞和髓源性抑制细胞（MDSC）以及肿瘤细胞上表达。C5a可以刺激中性粒细胞产生炎性介质，也可以募集MDSC等免疫抑制细胞形成免疫抑制微环境，促进肿瘤的生长和转移，从而在肿瘤的发生发展中起到重要的作用。C5AR1已成为肿瘤治疗的新靶点，C5AR1靶向药与免疫检查点抑制剂联用能够起到协同抑制肿瘤的作用。就C5AR1的基本信息，促进肿瘤发生、生长和转移的机制，以及以C5AR1为靶点的抗肿瘤药的开发现状进行综述，以期为后续的机制研究、药物开发提供参考。
ABSTRACT
Objective:To establish a mouse model of imiquimod (IMQ)-induced chronic psoriasis skin inflammation and to investigate the role of C5a/C5aR1 pathway in this process and the underlying mechanism.Methods:BALB/c mice were treated with IMQ cream or Vasline cream (control group) every other day for eight times to mimic the chronic skin inflammation. Psoriatic skin inflammation and pathological changes in the wild-type (C5aR1 + /+ ) mice and the mice with C5aR1 gene deletion (C5aR1 -/-) were monitored and analyzed. Epidermal proliferation (Ki67), keratin 6/14 expression and neutrophil infiltration in the skin lesions were observed with immunohistochemical (IHC) staining. qRCR was used to detect the expression of keratin 6/14 and related inflammatory cytokines. Flow cytometry was performed to measure the percentages of leukocytes, CD3 + T cells and IL-17A + γδTCR + T cells in local skin samples as well as IL-17A responses in draining lymph nodes. Results:IMQ treatment induced typical psoriatic skin inflammation, including scaling, erythema and thickness. Dysregulated epidermal proliferation, acanthosis, micro-abscesses, inflammatory cell infiltration and abnormal hyperplasia of dermal capillaries were observed after HE staining. Compared with the C5aR1 + /+ mice, the C5aR1 -/- mice showed significantly attenuated chronic skin inflammation, evidenced by decreased epidermal proliferation, down-regulated keratin 6/14 expression and alleviated neutrophil infiltration. Results of qPCR also indicated decreased expression of keratin 6/14, inflammatory cytokines (IFN-γ, MIP-1α, IL-1β and TNF-α) and IL-17-related cytokines (IL-6, IL-17A and IL-23) in skin samples of C5aR1 -/- mice. Moreover, the infiltration of leukocytes (CD45), CD3 + T cells and IL-17A + γδTCR + T cells in skin lesions as well as the percentages of IL-17A + , IL-17A + CD3 + T and IL-17A + γδTCR + T cells in draining lymph nodes were also decreased in C5aR1 -/- mice. Conclusions:This study suggested that IMQ treatment could induce chronic psoriasis skin inflammation in mice. C5a/C5aR1 signaling pathway mediates IMQ induced chronic skin inflammation via activating IL-17 producing cells. Targeting C5a/C5aR pathway would be a new strategy for the management of psoriasis.