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Regulatory role and mechanisms of myeloid TLR4 in anti-GBM glomerulonephritis
- Source :
- Cellular and Molecular Life Sciences
- Publication Year :
- 2021
- Publisher :
- Springer International Publishing, 2021.
-
Abstract
- 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 intlr4flox/floxandtlr4flox/flox−lysM−cremice by intravenous injection of the sheep anti-mouse GBM antibody. Compared to control mice, conditional disruption oftlr4from 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 myeloidtlr4markedly 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-1β and MCP-1. Importantly, deletion of myeloidtlr4suppressed T cell-mediated immune injury by shifting Th1 (CD4+IFNγ+) 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.
- Subjects :
- Male
Myeloid
Anti-GBM crescentic glomerulonephritis
Kidney Glomerulus
T cells
Kidney
Basement Membrane
Proinflammatory cytokine
Cellular and Molecular Neuroscience
Mice
Immune system
Glomerulonephritis
medicine
Animals
Myeloid Cells
IL-2 receptor
Molecular Biology
Pharmacology
Chemistry
Macrophages
Acute kidney injury
FOXP3
Cell Biology
Th1 Cells
medicine.disease
Mice, Inbred C57BL
Toll-Like Receptor 4
medicine.anatomical_structure
Cancer research
Molecular Medicine
Cytokines
Th17 Cells
Original Article
Female
Myeloid TLR4
Subjects
Details
- Language :
- English
- ISSN :
- 14209071 and 1420682X
- Volume :
- 78
- Issue :
- 19-20
- Database :
- OpenAIRE
- Journal :
- Cellular and Molecular Life Sciences
- Accession number :
- edsair.doi.dedup.....f196168b69a6db402a39ea291eae3c51