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However, what controls their activation in the skin is unknown. Here, we report that increased stiffness inhibits the production of IFN-I by pDCs. Mechanistically, mechanosensing activates stress pathways including NRF2, which induces the pentose phosphate pathway and reduces pyruvate levels, a product necessary for pDC responses. Modulating NRF2 activity in vivo controlled the pDC response, leading to resolution or chronic induction of IFN-I in the skin. In systemic sclerosis (SSc) patients, although NRF2 was induced in skin-infiltrating pDCs, as compared with blood pDCs, the IFN response was maintained. We observed that CXCL4, a profibrotic chemokine elevated in fibrotic skin, was able to overcome stiffness-mediated IFN-I inhibition, allowing chronic IFN-I responses by pDCs in the skin. Hence, these data identify a novel regulatory mechanism exerted by the skin microenvironment and identify points of dysregulation of this mechanism in patients with skin inflammation and fibrosis.<\/jats:p>","DOI":"10.1084\/jem.20240852","type":"journal-article","created":{"date-parts":[[2024,11,28]],"date-time":"2024-11-28T02:20:47Z","timestamp":1732760447000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":14,"title":["Mechanosensing regulates pDC activation in the skin through NRF2 activation"],"prefix":"10.1084","volume":"222","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6000-7517","authenticated-orcid":true,"given":"Vidyanath","family":"Chaudhary","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03zjqec80","id-type":"ROR","asserted-by":"publisher"}],"name":"HSS Research Institute, Inflammation and Autoimmunity Program, Hospital for Special Surgery 1 , New York, NY,","place":["USA"]},{"name":"Weill Cornell Medical College of Cornell University 2 Department of Microbiology and Immunology, , New York, NY,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7351-2096","authenticated-orcid":true,"given":"Bikash","family":"Mishra","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03zjqec80","id-type":"ROR","asserted-by":"publisher"}],"name":"HSS Research Institute, Inflammation and Autoimmunity Program, Hospital for Special Surgery 1 , New York, NY,","place":["USA"]},{"name":"Immunology and Microbial Pathogenesis Program, Graduate School of Medical Sciences, Weill Cornell Medicine 3 , New York, NY,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2319-0444","authenticated-orcid":true,"given":"Marie Dominique","family":"Ah Kioon","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03zjqec80","id-type":"ROR","asserted-by":"publisher"}],"name":"HSS Research Institute, Inflammation and Autoimmunity Program, Hospital for Special Surgery 1 , New York, NY,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2986-6249","authenticated-orcid":true,"given":"Yong","family":"Du","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03zjqec80","id-type":"ROR","asserted-by":"publisher"}],"name":"HSS Research Institute, Inflammation and Autoimmunity Program, Hospital for Special Surgery 1 , New York, NY,","place":["USA"]},{"name":"Weill Cornell Medical College of Cornell University 2 Department of Microbiology and Immunology, , New York, NY,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9951-0646","authenticated-orcid":true,"given":"Lionel B.","family":"Ivashkiv","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03zjqec80","id-type":"ROR","asserted-by":"publisher"}],"name":"HSS Research Institute, Inflammation and Autoimmunity Program, Hospital for Special Surgery 1 , New York, NY,","place":["USA"]},{"name":"Immunology and Microbial Pathogenesis Program, Graduate School of Medical Sciences, Weill Cornell Medicine 3 , New York, NY,","place":["USA"]},{"id":[{"id":"https:\/\/ror.org\/03zjqec80","id-type":"ROR","asserted-by":"publisher"}],"name":"David Z. 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