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

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...

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Bibliographic Details
Published in:Journal of autoimmunity 2024-09, Vol.148, p.103293, Article 103293
Main Authors: Yang, Wenxian, Bai, Xiaoyuan, Jia, Xiaoxiao, Li, Huizi, Min, Jie, Li, Heqiao, Zhang, Haoran, Zhou, Jianjing, Zhao, Yuna, Liu, Wenjun, Xin, Haiming, Sun, Lei
Format: Article
Language:English
Subjects:
ACE2
Angiotensin-Converting Enzyme 2 - metabolism
Animals
Antibodies, Monoclonal - pharmacology
Antibodies, Monoclonal - therapeutic use
Basigin - immunology
Basigin - metabolism
CD147
Cell Proliferation
Cyclophilin A - metabolism
Cytokines - metabolism
Disease Models, Animal
Extracellular cyclophilin A
Female
Humans
Inflammation - immunology
Inflammation - metabolism
Keratinocytes - immunology
Keratinocytes - metabolism
Male
Mice
Protein Binding
Psoriasis
Psoriasis - immunology
Psoriasis - metabolism
Signal Transduction
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Summary: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. •eCypA is highly expressed in patients with psoriasis and associated with psoriasis-like skin inflammation.•ACE2 is an alternative receptor for eCypA that activates JAK1/STAT3 signaling to mediate cytokine expression.•The eCypA-CD147 interaction promotes PI3K/AKT signaling-mediated keratinocyte proliferation.•Binding of eCypA to ACE2 and CD147 is blocked using a specific antibody against eCypA.
ISSN:0896-8411
1095-9157
1095-9157
DOI:10.1016/j.jaut.2024.103293