PDF(Pubmed)
Abstract：
Macrophages are a rich source of macrophage migration inhibitory factor (MIF). It is well established that macrophages and MIF play a pathogenic role in anti-glomerular basement membrane crescentic glomerulonephritis (anti-GBM CGN). However, whether macrophages mediate anti-GBM CGN via MIF-dependent mechanism remains unexplored, which was investigated in this study by specifically deleting MIF from macrophages in MIFf/f-lysM-cre mice. We found that compared to anti-GBM CGN induced in MIFf/f control mice, conditional ablation of MIF in macrophages significantly suppressed anti-GBM CGN by inhibiting glomerular crescent formation and reducing serum creatinine and proteinuria while improving creatine clearance. Mechanistically, selective MIF depletion in macrophages largely inhibited renal macrophage and T cell recruitment, promoted the polarization of macrophage from M1 towards M2 via the CD74/NF-κB/p38MAPK-dependent mechanism. Unexpectedly, selective depletion of macrophage MIF also significantly promoted Treg while inhibiting Th1 and Th17 immune responses. In summary, MIF produced by macrophages plays a pathogenic role in anti-GBM CGN. Targeting macrophage-derived MIF may represent a novel and promising therapeutic approach for the treatment of immune-mediated kidney diseases.
摘要：
巨噬细胞是巨噬细胞迁移抑制因子(MIF)的丰富来源。众所周知，巨噬细胞和MIF在抗肾小球基底膜新月体肾小球肾炎（抗GBMCGN）中起致病作用。然而,巨噬细胞是否通过MIF依赖性机制介导抗GBMCGN仍有待探索，在这项研究中，通过从MIFf/f-lysM-cre小鼠的巨噬细胞中特异性删除MIF进行了研究。我们发现，与MIFf/f对照小鼠诱导的抗GBMCGN相比，巨噬细胞中MIF的条件性消融通过抑制肾小球新月体形成和减少血清肌酐和蛋白尿,同时改善肌酸清除率,显著抑制抗GBMCGN.机械上,巨噬细胞中的选择性MIF消耗在很大程度上抑制了肾巨噬细胞和T细胞募集，通过CD74/NF-κB/p38MAPK依赖性机制促进巨噬细胞从M1向M2的极化。出乎意料的是,巨噬细胞MIF的选择性消耗也显著促进Treg,同时抑制Th1和Th17免疫应答。总之,巨噬细胞产生的MIF在抗GBMCGN中起致病作用。靶向巨噬细胞衍生的MIF可能代表用于治疗免疫介导的肾脏疾病的新颖且有前途的治疗方法。
