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Published on: June 8, 2022
Intrinsic renal cell and leukocyte-derived TLR4 aggravate experimental anti-MPO glomerulonephritis
Shaun A Summers1, Betty S van der Veen, Kim M O'Sullivan
1Department of Medicine, Centre for Inflammatory Diseases, Monash University, Clayton, Victoria, Australia.
Abstract:
Antimyeloperoxidase antibodies can cause crescentic glomerulonephritis and pulmonary hemorrhage. Toll-like receptors (TLRs) respond to infectious agents activating host defenses, whereas infections potentially initiate disease and provoke relapses. Neutrophils were found to be key effector cells of injury in experimental models, as disease does not occur in their absence and injury is enhanced by lipopolysaccharide (LPS). In this study, highly purified LPS (a pure TLR4 ligand) acted with antimyeloperoxidase antibodies to synergistically increase kidney and lung neutrophil recruitment and functional injury; effects abrogated in TLR4-deficient mice. Increased kidney TLR4 expression after stimulation predominantly occurred in glomerular endothelial cells. Enhanced glomerular neutrophil recruitment correlated with increased kidney mRNA expression of CXCL1 and CXCL2 (homologs of human CXCL8), whereas their preemptive neutralization decreased neutrophil recruitment. Disease induction in bone marrow chimeric mice showed that TLR4 in both bone marrow and renal parenchymal cells is required for maximal neutrophil recruitment and glomerular injury. Further studies in human glomerular cell lines stimulated with LPS found that glomerular endothelial cells were the prominent sources of CXCL8. Thus, our results define a role for TLR4 expression in bone marrow-derived and glomerular endothelial cells in neutrophil recruitment and subsequent functional and histological renal injury in experimental antimyeloperoxidase glomerulonephritis.
Insights
Toll-like receptor 4 (TLR4) activation by lipopolysaccharide (LPS) synergizes with anti-myeloperoxidase antibodies to drive kidney and lung injury. This TLR4-mediated neutrophil recruitment is crucial for experimental crescentic glomerulonephritis.
Area of Science:
- Nephrology
- Immunology
- Pathology
Background:
- Antimyeloperoxidase antibodies cause crescentic glomerulonephritis and pulmonary hemorrhage.
- Toll-like receptors (TLRs) mediate host defense against infections, which can trigger autoimmune diseases.
- Neutrophils are key effector cells in experimental models of anti-myeloperoxidase glomerulonephritis.
Purpose of the Study:
- To investigate the role of Toll-like receptor 4 (TLR4) in experimental anti-myeloperoxidase glomerulonephritis.
- To elucidate the mechanisms of neutrophil recruitment and injury in this disease model.
Main Methods:
- Used lipopolysaccharide (LPS), a TLR4 ligand, in conjunction with anti-myeloperoxidase antibodies in wild-type and TLR4-deficient mice.
- Assessed neutrophil recruitment and functional injury in kidneys and lungs.
- Investigated TLR4 expression in kidney cells and chemokine production (CXCL1, CXCL2, CXCL8).
- Employed bone marrow chimeric mice and human glomerular cell lines.
Main Results:
- Highly purified LPS synergistically increased kidney and lung neutrophil recruitment and injury with anti-myeloperoxidase antibodies.
- These effects were abrogated in TLR4-deficient mice, indicating TLR4 dependence.
- Increased kidney TLR4 expression was observed in glomerular endothelial cells.
- Enhanced neutrophil recruitment correlated with increased CXCL1 and CXCL2 expression.
- TLR4 in both bone marrow-derived and renal parenchymal cells was required for maximal injury.
- Human glomerular endothelial cells were identified as major sources of CXCL8.
Conclusions:
- TLR4 plays a critical role in mediating neutrophil recruitment and subsequent renal injury in experimental anti-myeloperoxidase glomerulonephritis.
- Glomerular endothelial cells and bone marrow-derived cells expressing TLR4 are essential for disease pathogenesis.
- Targeting TLR4 or its downstream signaling pathways may offer therapeutic strategies for anti-myeloperoxidase glomerulonephritis.
