| First Author | Chen J | Year | 2022 |
| Journal | Adv Sci (Weinh) | Volume | 9 |
| Issue | 18 | Pages | e2200668 |
| PubMed ID | 35484716 | Mgi Jnum | J:360469 |
| Mgi Id | MGI:7797595 | Doi | 10.1002/advs.202200668 |
| Citation | Chen J, et al. (2022) Single-cell RNA Sequencing Identified Novel Nr4a1(+) Ear2(+) Anti-Inflammatory Macrophage Phenotype under Myeloid-TLR4 Dependent Regulation in Anti-Glomerular Basement Membrane (GBM) Crescentic Glomerulonephritis (cGN). Adv Sci (Weinh) 9(18):e2200668 |
| abstractText | Previously, this study demonstrates the critical role of myeloid specific TLR4 in macrophage-mediated progressive renal injury in anti-glomerular basement membrane (anti-GBM) crescentic glomerulonephritis (cGN); however, the underlying mechanism remains largely unknown. In this study, single-cell RNA sequencing (scRNA-seq), pseudotime trajectories reconstruction, and motif enrichment analysis are used, and macrophage diversity in anti-GBM cGN under tight regulation of myeloid-TLR4 is uncovered. Most significantly, a myeloid-TLR4 deletion-induced novel reparative macrophage phenotype (Nr4a1(+) Ear2+) with significant upregulated anti-inflammatory and tissue repair-related signaling is discovered, thereby suppressing the M1 proinflammatory responses in anti-GBM cGN. This is further demonstrated in vitro that deletion of TLR4 from bone marrow-derived macrophages (BMDMs) induces the Nr4a1/Ear2-expressing anti-inflammatory macrophages while blocking LPS-stimulated M1 proinflammatory responses. Mechanistically, activation of the Nr4a1/Ear2-axis is recognized as a key mechanism through which deletion of myeloid-TLR4 promotes the anti-inflammatory macrophage differentiation in vivo and in vitro. This is confirmed by specifically silencing macrophage Nr4a1 or Ear2 to reverse the anti-inflammatory effects on TLR4 deficient BMDMs upon LPS stimulation. In conclusion, the findings decode a previously unidentified role for a myeloid-TLR4 dependent Nr4a1/Ear2 negative feedback mechanism in macrophage-mediated progressive renal injury, implying that activation of Nr4a1-Ear2 axis can be a novel and effective immunotherapy for anti-GBM cGN. |
