Institute of Infectious Diseases, Shenzhen Bay Laboratory, Shenzhen, Guangdong, 518107, China; CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China; Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology & Visual Sciences Key Laboratory, Beijing, 100730, China.
Institute of Infectious Diseases, Shenzhen Bay Laboratory, Shenzhen, Guangdong, 518107, China; CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China.
J Autoimmun. 2024 Sep;148:103293. doi: 10.1016/j.jaut.2024.103293. Epub 2024 Aug 2.
Psoriasis is a chronic, proliferative, and inflammatory skin disease closely associated with inflammatory cytokine production. Cyclophilin A (CypA) is an important proinflammatory factor; however, its role in psoriasis remains unclear. The present data indicate that CypA levels are increased in the lesion skin and serum of patients with psoriasis, which is positively correlated with the psoriasis area severity index. Furthermore, extracellular CypA (eCypA) triggered psoriasis-like inflammatory responses in keratinocytes. Moreover, anti-CypA mAb significantly reduced pathological injury, keratinocyte proliferation, cytokine expression in imiquimod-induced mice. Notably, the therapeutic effect of anti-CypA mAb was better than that of the clinically used anti-IL-17A mAb and methotrexate. Mechanistically, eCypA binds to ACE2 and CD147 and is blocked by anti-CypA mAb. eCypA not only induces the dimerization and phosphorylation of ACE2 to trigger the JAK1/STAT3 signaling pathway for cytokine expression but also interacts with CD147 to promote PI3K/AKT/mTOR signaling-mediated keratinocyte proliferation. These findings demonstrate that the binding of eCypA to ACE2 and CD147 cooperatively triggers psoriasis-like inflammation and anti-CypA mAb is a promising candidate for the treatment of psoriasis.
银屑病是一种与炎症细胞因子产生密切相关的慢性增殖性炎症性皮肤病。亲环素 A（CypA）是一种重要的促炎因子；然而，其在银屑病中的作用尚不清楚。本研究数据表明，银屑病患者皮损皮肤和血清中的 CypA 水平升高，且与银屑病面积严重指数呈正相关。此外，细胞外 CypA（eCypA）可引发角质形成细胞的银屑病样炎症反应。此外，抗 CypA mAb 可显著减轻咪喹莫特诱导的小鼠的病理性损伤、角质形成细胞增殖和细胞因子表达。值得注意的是，抗 CypA mAb 的治疗效果优于临床使用的抗 IL-17A mAb 和甲氨蝶呤。在机制上，eCypA 与 ACE2 和 CD147 结合，并被抗 CypA mAb 阻断。eCypA 不仅诱导 ACE2 的二聚化和磷酸化，从而触发细胞因子表达的 JAK1/STAT3 信号通路，还与 CD147 相互作用，促进 PI3K/AKT/mTOR 信号通路介导的角质形成细胞增殖。这些发现表明，eCypA 与 ACE2 和 CD147 的结合共同引发银屑病样炎症，抗 CypA mAb 是治疗银屑病的有前途的候选药物。
