Regulatory role and mechanisms of myeloid TLR4 in anti-GBM glomerulonephritis

Myeloid cells and TLR4 play a critical role in acute kidney injury. This study investigated the regulatory role and mechanisms of myeloid TLR4 in experimental anti-glomerular basement membrane (GBM) glomerulonephritis (GN). Anti-GBM GN was induced in tlr4(flox/flox) and tlr4(flox/flox-lysM-cre) mice by intravenous injection of the sheep anti-mouse GBM antibody. Compared to control mice, conditional disruption of tlr4 from myeloid cells, largely macrophages (> 85%), suppressed glomerular crescent formation and attenuated progressive renal injury by lowering serum creatinine and 24-h urine protein excretion while improving creatinine clearance. Mechanistically, deletion of myeloid tlr4 markedly inhibited renal infiltration of macrophages and T cells and resulted in a shift of infiltrating macrophages from F4/80(+)iNOS(+) M1 to F4/80(+)CD206(+) M2 phenotype and inhibited the upregulation of renal proinflammatory cytokines IL-1 beta and MCP-1. Importantly, deletion of myeloid tlr4 suppressed T cell-mediated immune injury by shifting Th1 (CD4(+)IFN gamma(+)) and Th17 (CD4(+)IL-17a(+)) to Treg (CD4(+)CD25(+)FoxP3(+)) immune responses. Transcriptome analysis also revealed that disrupted myeloid TLR4 largely downregulated genes involving immune and cytokine-related pathways. Thus, myeloid TLR4 plays a pivotal role in anti-GBM GN by immunological switching from M1 to M2 and from Th1/Th17 to Treg and targeting myeloid TLR4 may be a novel therapeutic strategy for immune-mediated kidney diseases.

Automated summary

The study found that deletion of TLR4 from myeloid cells can suppress renal injury caused by anti-GBM GN by regulating immune cell types and related signaling pathways.