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
School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen 518057, China.
Proc Natl Acad Sci U S A. 2025 Mar 18;122(11):e2418739122. doi: 10.1073/pnas.2418739122. Epub 2025 Mar 13.
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 αTAT1 phosphorylation and α-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, αTAT1 phosphorylation, and α-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/αTAT1/α-tubulin cascade.
巨噬细胞在肾脏疾病中的重要性已得到充分证实；然而，巨噬细胞浸润到受损肾脏的潜在机制尚不完全清楚。RGMb是排斥导向分子（RGM）家族的成员。RGMb可在细胞表面表达，但大部分RGMb定位于细胞内。在各种免疫细胞类型中，巨噬细胞表达的RGMb水平最高，但RGMb在巨噬细胞中的生物学功能在很大程度上仍不清楚。我们发现，RGMb在体外促进巨噬细胞迁移，在体内，RGMb增强巨噬细胞向受损肾脏的浸润，并加重小鼠的肾脏炎症和损伤。机制上，RGMb在细胞内与TAB1结合，促进TRAF6泛素连接酶与TAB1之间的相互作用，从而促进TRAF6介导的TAK1的K63连接的多聚泛素化和磷酸化，随后增加αTAT1磷酸化和α-微管蛋白乙酰化。细胞骨架的这些变化在体外和体内均促进了巨噬细胞迁移。巨噬细胞中Rgmb的缺失显著降低TAK1磷酸化、αTAT1磷酸化和α-微管蛋白乙酰化，并减轻肾脏损伤期间的巨噬细胞浸润、肾脏炎症、肾小管损伤和间质纤维化。我们的结果表明，巨噬细胞RGMb通过TRAF6-TAB1-TAK1/αTAT1/α-微管蛋白级联增加巨噬细胞浸润，从而促进肾脏疾病。
