{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:33:23Z","timestamp":1792787603844,"version":"4.5.0"},"reference-count":42,"publisher":"American Society for Clinical Investigation","issue":"19","license":[{"start":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T00:00:00Z","timestamp":1791417600000},"content-version":"vor","delay-in-days":63,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Natural Science Foundation of China","award":["82371709"],"award-info":[{"award-number":["82371709"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Zhejiang Provincial natural science foundation","award":["LHDMZ25H050002"],"award-info":[{"award-number":["LHDMZ25H050002"]}],"id":[{"id":"https:\/\/ror.org\/04aqat463","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,8]]},"abstract":"<jats:p>\n                    Obstructive nephropathy is a significant and preventable contributor to chronic kidney disease, yet no disease-modifying antifibrotic agents are currently available. We hypothesized that interferon regulatory factor 5 (IRF5) functions as a macrophage transcriptional regulator that directly transactivates matrix metalloproteinase 9 (MMP9) to initiate early extracellular matrix (ECM) remodeling. Analysis of 30 human obstructive nephropathy biopsy specimens demonstrated that IRF5\n                    <jats:sup>+<\/jats:sup>\n                    CD68\n                    <jats:sup>+<\/jats:sup>\n                    macrophage density increased progressively with fibrosis severity and correlated significantly with \u03b1-smooth muscle actin\u2013positive (\u03b1-SMA\n                    <jats:sup>+<\/jats:sup>\n                    ) areas. In the murine unilateral ureteral obstruction (UUO) model, both global and myeloid-specific\n                    <jats:italic>Irf5<\/jats:italic>\n                    deletion significantly attenuated collagen deposition, immune cell infiltration, and fibrotic gene expression compared with WT controls. Cleavage under targets and tagmentation (CUT&amp;Tag) analysis demonstrated that IRF5 directly binds the\n                    <jats:italic>Mmp9<\/jats:italic>\n                    enhancer region and increases chromatin accessibility. Consequently, myeloid-specific\n                    <jats:italic>Irf5<\/jats:italic>\n                    KO significantly reduced\n                    <jats:italic>Mmp9<\/jats:italic>\n                    mRNA and MMP9 protein levels. Pharmacological inhibition using the IRF5 inhibitor N5-1 mitigated established fibrosis, downregulated \u03b1-SMA and MMP9 expression, and reduced CD68\n                    <jats:sup>+<\/jats:sup>\n                    macrophage infiltration. These findings identify the IRF5\/MMP9 axis as a therapeutically targetable pathway driving macrophage-mediated ECM expansion and provide preclinical evidence supporting IRF5 inhibition as a potential treatment strategy for patients with obstructive nephropathy.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.201877","type":"journal-article","created":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T16:00:19Z","timestamp":1786032019000},"source":"Crossref","is-referenced-by-count":0,"title":["Interferon regulatory factor 5 in myeloid cells promotes obstructive nephropathy-induced renal fibrosis in vivo"],"prefix":"10.1172","volume":"11","author":[{"given":"Jia","family":"Wei","sequence":"first","affiliation":[{"name":"Department of Urology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Du","sequence":"additional","affiliation":[{"name":"Department of Urology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zixia","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Urology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pathology, Children\u2019s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Urology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zihao","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Urology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yidan","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of cardiovascular surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Urology and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2026,8,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2613.2010.00730.x"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ki.5000054"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-physiol-022516-034227"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1080\/0886022X.2022.2079528"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1080\/07853890.2022.2098374"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/s41581-019-0110-2"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1186\/s12882-020-01921-7"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2016050573"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.01597"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2017.02.006"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.88689"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.trsl.2015.06.018"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2009.86"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2024.10.012"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20162152"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2014.00430"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1990"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2007.01.090"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/nri1900"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/nature03308"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1006\/geno.2000.6206"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2014.07.034"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathol-020712-163930"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202309752"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/labinvest.2013.3"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2009.07.004"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2125"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1821"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1038\/nri1418"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1038\/nrc745"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.cellbio.17.1.463"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/s41581-021-00415-5"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2023.116116"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2010.090188"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2009.080983"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfw308"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1038\/labinvest.2013.3"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00015.2014"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1111\/apha.13317"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-24609-4"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0151999"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1172\/JCI120288"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/201877\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T18:02:07Z","timestamp":1791396127000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/201877"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,6]]},"references-count":42,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2026,8,18]]},"published-print":{"date-parts":[[2026,10,8]]}},"alternative-id":["10.1172\/jci.insight.201877"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.201877","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,6]]},"article-number":"e201877"}}