{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:21:02Z","timestamp":1792790462975,"version":"4.5.0"},"reference-count":41,"publisher":"American Society for Clinical Investigation","issue":"13","funder":[{"name":"National Institutes of Health (NIH) National Institute of Arthritis and Musculoskeletal and Skin (NIAMS), Scleroderma Foundation.","award":["AR42309,GM101279"],"award-info":[{"award-number":["AR42309,GM101279"]}]},{"DOI":"10.13039\/100001844","name":"Scleroderma Foundation","doi-asserted-by":"crossref","award":["SP# SP0034818"],"award-info":[{"award-number":["SP# SP0034818"]}],"id":[{"id":"10.13039\/100001844","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,7,12]]},"abstract":"<jats:p>Persistent fibrosis in multiple organs is the hallmark of systemic sclerosis (SSc). Recent genetic and genomic studies implicate TLRs and their damage-associated molecular pattern (DAMP) endogenous ligands in fibrosis. To test the hypothesis that TLR4 and its coreceptor myeloid differentiation 2 (MD2) drive fibrosis persistence, we measured MD2\/TLR4 signaling in tissues from patients with fibrotic SSc, and we examined the impact of MD2 targeting using a potentially novel small molecule. Levels of MD2 and TLR4, and a TLR4-responsive gene signature, were enhanced in SSc skin biopsies. We developed a small molecule that selectively blocks MD2, which is uniquely required for TLR4 signaling. Targeting MD2\/TLR4 abrogated inducible and constitutive myofibroblast transformation and matrix remodeling in fibroblast monolayers, as well as in 3-D scleroderma skin equivalents and human skin explants. Moreover, the selective TLR4 inhibitor prevented organ fibrosis in several preclinical disease models and mouse strains, and it reversed preexisting fibrosis. Fibroblast-specific deletion of TLR4 in mice afforded substantial protection from skin and lung fibrosis. By comparing experimentally generated fibroblast TLR4 gene signatures with SSc skin biopsy gene expression datasets, we identified a subset of SSc patients displaying an activated TLR4 signature. Together, results from these human and mouse studies implicate MD2\/TLR4-dependent fibroblast activation as a key driver of persistent organ fibrosis. The results suggest that SSc patients with high TLR4 activity might show optimal therapeutic response to selective inhibitors of MD2\/TLR4 complex formation.<\/jats:p>","DOI":"10.1172\/jci.insight.98850","type":"journal-article","created":{"date-parts":[[2018,7,11]],"date-time":"2018-07-11T11:01:22Z","timestamp":1531306882000},"source":"Crossref","is-referenced-by-count":134,"title":["TLR4-dependent fibroblast activation drives persistent organ fibrosis in skin and lung"],"prefix":"10.1172","volume":"3","author":[{"given":"Swati","family":"Bhattacharyya","sequence":"first","affiliation":[{"name":"Northwestern Scleroderma Program, Feinberg School of Medicine, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenxia","family":"Wang","sequence":"additional","affiliation":[{"name":"Northwestern Scleroderma Program, Feinberg School of Medicine, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenyi","family":"Qin","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of Illinois at Chicago, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4136-2070","authenticated-orcid":true,"given":"Kui","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry and the BioFrontiers Institute, University of Colorado Boulder, Boulder, Colorado, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Coulup","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry and the BioFrontiers Institute, University of Colorado Boulder, Boulder, Colorado, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sherry","family":"Chavez","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry and the BioFrontiers Institute, University of Colorado Boulder, Boulder, Colorado, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuangshang","family":"Jiang","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Tsinghua University, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirtee","family":"Raparia","sequence":"additional","affiliation":[{"name":"Feinberg School of Medicine, Northwestern University, Evanston, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucia Maria V.","family":"De Almeida","sequence":"additional","affiliation":[{"name":"Feinberg School of Medicine, Northwestern University, Evanston, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Stehlik","sequence":"additional","affiliation":[{"name":"Feinberg School of Medicine, Northwestern University, Evanston, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zenshiro","family":"Tamaki","sequence":"additional","affiliation":[{"name":"Northwestern Scleroderma Program, Feinberg School of Medicine, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9762-4818","authenticated-orcid":true,"given":"Hang","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry and the BioFrontiers Institute, University of Colorado Boulder, Boulder, Colorado, USA."},{"name":"School of Pharmaceutical Sciences, Tsinghua University, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Varga","sequence":"additional","affiliation":[{"name":"Northwestern Scleroderma Program, Feinberg School of Medicine, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2018,7,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2807"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2016-210645"},{"issue":"1","key":"B3","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1038\/nrrheum.2011.149","article-title":"Understanding fibrosis in systemic sclerosis: shifting paradigms, emerging opportunities","volume":"8","author":"Bhattacharyya","year":"2011","journal-title":"Nat Rev Rheumatol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1863"},{"key":"B5","doi-asserted-by":"crossref","DOI":"10.1155\/2010\/672395","article-title":"DAMPening inflammation by modulating TLR signalling","author":"Piccinini","year":"2010","journal-title":"Mediators Inflamm"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20090616"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.08.002"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1084\/jem.189.11.1777"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.201500188"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2013.2194"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1097\/CCM.0b013e3181e7c5c9"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2012.09.007"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3008264"},{"key":"B14","doi-asserted-by":"crossref","DOI":"10.1038\/ncomms11703","article-title":"Tenascin-C drives persistence of organ fibrosis","volume":"7","author":"Bhattacharyya","year":"2016","journal-title":"Nat Commun"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1038\/nm1663"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2009070722"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.jss.2009.09.053"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1002\/art.38901"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1520997112"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0114017"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0015615"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1021\/jm2003365"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1002\/anie.200461786"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1021\/ml100041f"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1200130109"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2012-201784"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1096\/fj.12-219378"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2012.02.004"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-60761-380-0_10"},{"issue":"1","key":"B30","doi-asserted-by":"crossref","DOI":"10.1007\/s11926-014-0474-z","article-title":"Emerging roles of innate immune signaling and toll-like receptors in fibrosis and systemic sclerosis","volume":"17","author":"Bhattacharyya","year":"2015","journal-title":"Curr Rheumatol Rep"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0002696"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/jid.2011.472"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1002\/art.39655"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1089\/wound.2017.0732"},{"key":"B35","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2014.00328","article-title":"Toll-like receptor-4 modulation for cancer immunotherapy","volume":"5","author":"Awasthi","year":"2014","journal-title":"Front Immunol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2014.22"},{"key":"B37","doi-asserted-by":"crossref","DOI":"10.1186\/1465-9921-10-126","article-title":"Inhibiting toll-like receptor 4 signaling ameliorates pulmonary fibrosis during acute lung injury induced by lipopolysaccharide: an experimental study","volume":"10","author":"He","year":"2009","journal-title":"Respir Res"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4192"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2011.09.019"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200809044"},{"key":"B41","doi-asserted-by":"crossref","DOI":"10.1186\/s12931-015-0220-8","article-title":"Second harmonic generation microscopy reveals altered collagen microstructure in usual interstitial pneumonia versus healthy lung","volume":"16","author":"Kottmann","year":"2015","journal-title":"Respir Res"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/98850\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T12:59:11Z","timestamp":1779195551000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/98850"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,7,12]]},"references-count":41,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2018,7,12]]},"published-print":{"date-parts":[[2018,7,12]]}},"alternative-id":["10.1172\/jci.insight.98850"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.98850","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,7,12]]},"article-number":"e98850"}}