Toll-like receptor 4 ligation on intrinsic renal cells contributes to the induction of antibody-mediated glomerulonephritis via CXCL1 and CXCL2.
Autoimmune diseases such as glomerulonephritis are exacerbated by infection. This study examined the effect of the Toll-like receptor 4 (TLR4) ligand lipid A on the development of heterologous nephrotoxic nephritis. Administration of nephrotoxic antibody resulted in significant glomerular neutrophil infiltration and albuminuria only when a TLR4 ligand was administered simultaneously. The contribution of TLR4 on renal cells and circulating leukocytes was assessed. Bone marrow chimeras were constructed with TLR4 only on renal cells or bone marrow-derived cells. The administration of nephrotoxic serum and lipid A caused a neutrophil influx in both chimeric groups greater than in sham chimeras that were totally TLR4 deficient but significantly less than in sham chimeras that were totally TLR4 sufficient. Both chimeric groups had greater albuminuria than totally TLR4-deficient sham chimeras; however, the chimeras with TLR4 only on intrinsic renal cells had significantly less than the sham positive group. In situ hybridization showed expression of TLR4 mRNA in mesangial cells and glomerular epithelial cells. For investigation of the potential mechanism by which renal cells could contribute to disease exacerbation, mesangial cells were cultured and found to express mRNA for TLR4, and stimulation of wild-type and TLR4-deficient mesangial cells with LPS caused production of CXC chemokines by wild-type cells only. Treatment of chimeras with TLR4 present only on intrinsic renal cells with anti-CXCL1 and anti-CXCL2 antibody before disease induction significantly reduced renal neutrophil infiltration. These results show that TLR4 on both circulating leukocytes and intrinsic renal cells contributes to the inflammatory effects of antibody deposition within the glomerulus, which depends at least in part on the production of CXC chemokines by intrinsic renal cells.
Brown
Heather J
HJ
Department of Nephrology and Transplantation, 5th Floor Thomas Guy House, Guy's Hospital, St. Thomas Street, London, UK. heather.brown@kcl.ac.uk
Lock
Helen R
HR
Wolfs
Tim G A M
TG
Buurman
Wim A
WA
Sacks
Steven H
SH
Robson
Michael G
MG
D000419:Albuminuria / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D054360:Chemokine CXCL1 / Q000276:immunology / Q000378:metabolism*; D054426:Chemokine CXCL2 / Q000276:immunology / Q000378:metabolism*; D005260:Female; D005921:Glomerulonephritis / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D007074:Immunoglobulin G / Q000378:metabolism / Q000494:pharmacology; D008024:Ligands; D008050:Lipid A / Q000494:pharmacology; D008297:Male; D050527:Mesangial Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009504:Neutrophils / Q000276:immunology / Q000473:pathology; D012720:Severity of Illness Index; D012756:Sheep; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; C475895:Cxcl1 protein, mouse; C404915:Cxcl2 protein, mouse; D007074:Immunoglobulin G; D008024:Ligands; D008050:Lipid A; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4