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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,3,18]]},"abstract":"<jats:p>The importance of macrophages in kidney diseases has been well established; however, the mechanisms underlying the infiltration of macrophages into injured kidneys are not well understood. RGMb is a member of the repulsive guidance molecule (RGM) family. RGMb can be expressed on the cell surface but a large portion of RGMb is localized intracellularly. Among various immune cell types, macrophages express the highest levels of RGMb, but the biological functions of RGMb in macrophages remain largely unknown. We find that RGMb promoted macrophage migration in vitro and that in vivo, RGMb enhanced infiltration of macrophages into injured kidneys and aggravated kidney inflammation and injury in mice. Mechanistically, RGMb bound to TAB1 inside the cell and facilitated the interaction between TRAF6 ubiquitin ligase and TAB1, thereby promoting TRAF6-mediated K63-linked polyubiquitination and phosphorylation of TAK1, followed by increased \u03b1TAT1 phosphorylation and \u03b1-tubulin acetylation. The resulting changes in the cytoskeleton promoted macrophage migration in vitro and in vivo. Deletion of Rgmb in macrophages markedly reduced TAK1 phosphorylation, \u03b1TAT1 phosphorylation, and \u03b1-tubulin acetylation and attenuated macrophage infiltration, renal inflammation, tubular injury, and interstitial fibrosis during kidney injury. Our results suggest that macrophage RGMb promotes kidney disease by increasing macrophage infiltration via the TRAF6-TAB1-TAK1\/\u03b1TAT1\/\u03b1-tubulin cascade.<\/jats:p>","DOI":"10.1073\/pnas.2418739122","type":"journal-article","created":{"date-parts":[[2025,3,13]],"date-time":"2025-03-13T14:35:01Z","timestamp":1741876501000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":8,"title":["RGMb drives macrophage infiltration to aggravate kidney disease"],"prefix":"10.1073","volume":"122","author":[{"given":"Yonglun","family":"Kong","sequence":"first","affiliation":[{"name":"School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong","place":["Hong Kong, China"]},{"name":"Shenzhen Research Institute, The Chinese University of Hong Kong","place":["Shenzhen, 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Li, L. Ye, H. G. Kynaston, W. G. Jiang, Repulsive guidance molecules, novel bone morphogenetic protein co-receptors, are key regulators of the growth and aggressiveness of prostate cancer cells. Int. J. Oncol. 40, 544\u2013550 (2012).","journal-title":"Int. J. Oncol."},{"key":"e_1_3_4_56_2","doi-asserted-by":"publisher","DOI":"10.1023\/A:1008942828960"},{"key":"e_1_3_4_57_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-022-00936-4"},{"key":"e_1_3_4_58_2","unstructured":"Y. Xia Y. Kong M. Yue Gene expression profile at single cell level of kidneys from RGMb flox\/flox Lyz2 cre (RGMb mKO) & Lyz2 cre (Ctrl) mice with or with cisplatin (20 mg\/KG body weight for 72 h). Gene Expression Omnibus. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE268818. 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