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Targeting Th17 cells holds promise for therapeutic innovation. While the core cytokine signaling networks driving Th17 differentiation have been extensively characterized, the roles of non-canonical secreted factors in Th17 polarization and pathogenicity remain incompletely understood. Here, we found that Serpine1 was preferentially induced in Th17 cells. Genetic ablation of Serpine1 inhibited Th17 cell polarization in vitro, reproducing the phenotype observed with pharmaceutical inhibition of PAI-1, the product of Serpine1. Furthermore, in a TLR7\/8-driven inflammatory skin model induced by imiquimod (IMQ), deletion or inhibition of Serpine1 significantly attenuated disease severity and reduced skin inflammation. Notably, this protective effect was also recapitulated in T cell-specific Serpine1 conditional knockout mice, confirming a T cell-intrinsic role for Serpine1 and ruling out non-T-cell-autonomous effects. Collectively, our results revealed a critical and T cell-intrinsic role for Serpine1 in Th17 differentiation and autoimmune pathology, suggesting that Serpine1\/PAI-1 may contribute to Th17-mediated inflammation.<\/jats:p>","DOI":"10.1093\/jimmun\/vkag076","type":"journal-article","created":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T13:14:42Z","timestamp":1778591682000},"source":"Crossref","is-referenced-by-count":0,"title":["Serpine1 regulates Th17 cell differentiation and exacerbates IMQ-induced skin inflammation"],"prefix":"10.1093","volume":"215","author":[{"given":"Kaidireya","family":"Saimaier","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ling","family":"Xie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jie","family":"Lv","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guangyu","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sanxing","family":"Han","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5938-5510","authenticated-orcid":false,"given":"Chunliang","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7922-9785","authenticated-orcid":false,"given":"Changsheng","family":"Du","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2026,5,12]]},"reference":[{"key":"2026051209124711100_vkag076-B1","doi-asserted-by":"crossref","first-page":"1945","DOI":"10.1001\/jama.2020.4006","article-title":"Pathophysiology, 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