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Although the pathogenesis of SSc is poorly understood, increasing evidence suggests that interleukins (IL)\u20104 and\u2009\u2212\u200913 contribute to the pathogenesis of skin fibrosis by promoting collagen production and myofibroblast differentiation. Signal transducers and activators of transcription 6 (STAT6) is one of the most important downstream transcription factors activated by both IL\u20104 and IL\u201013. However, it is not completely understood whether STAT6 plays a role during the pathogenesis of skin fibrosis in SSc. In this study, we observed increased STAT6 phosphorylation in fibrotic skin samples collected from SSc patients as well as bleomycin\u2010injected murine mice. Knockout of Stat6 in mice significantly (1) suppressed the expression of fibrotic cytokines including\n                    <jats:italic>Il13, Il17, Il22, Ccl2<\/jats:italic>\n                    , and the alternatively activated macrophage marker\n                    <jats:italic>Cd206<\/jats:italic>\n                    ; (2) reduced the production of collagen and fibronectin, and (3) attenuated late\u2010stage skin fibrosis and inflammation induced by bleomycin. Consistently, mice treated with STAT6 inhibitor AS1517499 also attenuated skin fibrosis on day 28. In addition, a co\u2010culture experiment demonstrated that skin epithelial cells with STAT6 knockdown had reduced cytokine expression in response to IL\u20104\/IL\u201013, and subsequently attenuated fibrotic protein expression in skin fibroblasts. On the other side, STAT6 depletion in skin fibroblasts attenuated IL\u20104\/IL\u201013\u2010induced cytokine and fibrotic marker expression, and reduced\n                    <jats:italic>CXCL2<\/jats:italic>\n                    expression in co\u2010cultured keratinocytes. In summary, our study highlighted an important yet not fully understood role of STAT6 in skin fibrosis by driving innate inflammation and differentiation of alternatively activated macrophages in response to injury.\n                  <\/jats:p>","DOI":"10.1096\/fj.202200994r","type":"journal-article","created":{"date-parts":[[2023,1,11]],"date-time":"2023-01-11T10:26:23Z","timestamp":1673432783000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["<scp>STAT6<\/scp>\n                    suppression prevents bleomycin\u2010induced dermal fibrosis"],"prefix":"10.1096","volume":"37","author":[{"given":"Jingjing","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Geriatrics The Fourth Affiliated Hospital of Nanjing Medical University  Nanjing Jiangsu China"},{"name":"Department of Biochemistry and Molecular Biology, McGovern Medical School The University of Texas Health Science Center at Houston  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