RGMb drives macrophage infiltration to aggravate kidney disease

• 成果类型: Article
• 署名作者: Kong, Yonglun; Yue, Ming; Xu, Chunhua; Zhang, Jing; Hong, Huiling; Lu, Jiahuan; Wang, Yang; Zhang, Xiaoyi; Chen, Qiuju; Yang, Chen; Liu, Hua - Feng; Qin, Jinzhong; Zhou, Jingying; Lee, Nam Y.; Lin, Bin; Tian, Xiaoyu; Freeman, Gordon J.; Xia, Yin
• 署名单位: Chinese University of Hong Kong; CUHK Shenzhen Research Institute; The Chinese University of Hong Kong, Shenzhen; University of Hong Kong; University of Hong Kong; Longgang District Central Hospital of Shenzhen; Hong Kong Polytechnic University; Guangdong Medical University; Nanjing University; University of Arizona; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Chinese University of Hong Kong
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10368
• DOI: 10.1073/pnas.2418739122
• 发表日期: 2025-03-18
• 关键词: nf-kappa-b; tak1; kinase; apoptosis; GROWTH; injury; microtubules; activation; mechanisms; inhibitor

摘要

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 alpha TAT1 phosphorylation and alpha- 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, alpha TAT1 phosphorylation, and alpha- 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/alpha TAT1/alpha- tubulin cascade.