The binding of extracellular cyclophilin A to ACE2 and CD147 triggers psoriasis-like inflammation

作者：Wenxian Yang, Xiaoyuan Bai, Xiaoxiao Jia, Huizi Li, Jie Min, Heqiao Li, Haoran Zhang, Jianjing Zhou, Yuna Zhao, Wenjun Liu, Haiming Xin, Lei Sun · 发表于：Journal of Autoimmunity · 年份：2024 · DOI：10.1016/j.jaut.2024.103293 · 被引用次数：9 · 研究领域：Signaling Pathways in Disease、Reproductive System and Pregnancy、Pharmacological Effects of Natural Compounds

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.