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Semaphorin 4A (Sema4A), an immune semaphorin, is known to take part in T helper type 1\/17 differentiation and activation. However, Sema4A is also crucial for maintaining peripheral tissue homeostasis and its involvement in skin remains unknown. Here, we revealed that while Sema4A expression was pronounced in psoriatic blood lymphocytes and monocytes, it was downregulated in the keratinocytes of both psoriatic lesions and non-lesions compared to controls. Imiquimod application induced more severe dermatitis in Sema4A knockout (KO) mice compared to wild-type (WT) mice. The na\u00efve skin of Sema4A KO mice showed increased T cell infiltration and IL-17A expression along with thicker epidermis and distinct cytokeratin expression compared to WT mice, which are hallmarks of psoriatic non-lesions. Analysis of bone marrow chimeric mice suggested that Sema4A expression in keratinocytes plays a regulatory role in imiquimod-induced dermatitis. The epidermis of psoriatic non-lesion and Sema4A KO mice demonstrated mTOR complex 1 upregulation, and the application of mTOR inhibitors reversed the skewed expression of cytokeratins in Sema4A KO mice. Conclusively, Sema4A-mediated signaling cascades can be triggers for psoriasis and targets in the treatment and prevention of psoriasis.<\/jats:p>","DOI":"10.7554\/elife.97654","type":"journal-article","created":{"date-parts":[[2024,5,28]],"date-time":"2024-05-28T13:51:19Z","timestamp":1716904279000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.97654","source":"Crossref","is-referenced-by-count":5,"title":["Downregulation of semaphorin 4A in keratinocytes reflects the features of non-lesional psoriasis"],"prefix":"10.7554","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7632-6072","authenticated-orcid":true,"given":"Miki","family":"Kume","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/035t8zc32","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Dermatology, Course of Integrated Medicine, Graduate School of Medicine, Osaka University","place":["Osaka, 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