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Specifically, we find that keratinocyte proliferation and expression of protease-activated receptor 2 (PAR2) are early responses following lymphatic injury and regulate the expression of Th2-inducing cytokines, migration of Langerhans cells, and skin infiltration of Th2-differentiated T cells. Furthermore, inhibition of PAR2 activation with a small molecule inhibitor or the proliferation inhibitor teriflunomide (TF) prevents activation of keratinocytes stimulated with lymphedema fluid. Finally, topical TF is highly effective for decreasing swelling, fibrosis, and inflammation in a preclinical mouse model. Our findings suggest that lymphedema is a chronic inflammatory skin disease, and topically targeting keratinocyte activation may be a clinically effective therapy for this condition.<\/jats:p>","DOI":"10.1101\/2023.01.20.524936","type":"posted-content","created":{"date-parts":[[2023,1,21]],"date-time":"2023-01-21T06:20:19Z","timestamp":1674282019000},"source":"Crossref","is-referenced-by-count":2,"title":["Keratinocytes coordinate inflammatory responses and regulate development of secondary lymphedema"],"prefix":"10.64898","author":[{"given":"Hyeung Ju","family":"Park","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raghu P.","family":"Kataru","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinyeon","family":"Shin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriela D.","family":"Garc\u00eda Nores","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth M.","family":"Encarnacion","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark G.","family":"Klang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elyn","family":"Riedel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michelle","family":"Coriddi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph H.","family":"Dayan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Babak J.","family":"Mehrara","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2023012405050669000_2023.01.20.524936v1.1","doi-asserted-by":"publisher","DOI":"10.1177\/1358863X9700200408"},{"key":"2023012405050669000_2023.01.20.524936v1.2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0142(19981215)83:12B+<2776::AID-CNCR25>3.0.CO;2-V"},{"key":"2023012405050669000_2023.01.20.524936v1.3","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1146\/annurev-med-060116-022900","article-title":"Lymphedema: Pathogenesis and Novel Therapies","volume":"69","year":"2018","journal-title":"Annu Rev Med"},{"key":"2023012405050669000_2023.01.20.524936v1.4","doi-asserted-by":"publisher","DOI":"10.1007\/s10549-006-9297-6"},{"key":"2023012405050669000_2023.01.20.524936v1.5","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1097\/PRS.0000000000007783","article-title":"Surgical Treatment of Lymphedema: A Systematic Review and Meta-Analysis of Controlled Trials. 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