Toll-Like Receptor 4 Ligation on Intrinsic Renal Cells Contributes to the Induction of Antibody-Mediated Glomerulonephritis via CXCL1 and CXCL2

Abstract

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.

Toll-Like Receptor 4 Stimulation Triggers Crescentic Glomerulonephritis by Multiple Mechanisms Including a Direct Effect on Renal Cells

“…It exacerbates the neutrophil influx and proteinuria induced by passively administered glomerular-binding antibody. 11,12 The current study differs from our previous reports because, unlike heterologous nephrotoxic nephritis, the autologous phase is a model in which progressive disease occurs, and histological features closely resemble those seen in human glomerulonephritis.…”

“…We have recently established that stimulation of TLR2 and TLR4 can trigger disease in the heterologous phase of nephrotoxic nephritis. 11,12 This is a model of neutrophil-mediated acute glomerular inflammation induced by passively administered glomerular binding antibody. 13 For both TLR2 and TLR4, we demonstrated that stimulation of renal cell TLRs played an important role.…”

Exacerbation of diabetic nephropathy by hyperlipidaemia is mediated by Toll-like receptor 4 in mice

“…TLR4 signalling also plays an important role in the development of various kidney diseases, yet the role of TLR4 in diabetic glomerulopathy or hyperlipidaemiainduced kidney damage remains to be elucidated [8][9][10][11][12][13]. Recently, Burkhardt et al and Bouma et al reported that serum S100A8/A9 complex concentrations were elevated in patients with diabetes [33,34].…”

“…Functional analysis of S100A8 protein production in diabetic mice is currently under way in our laboratory. Candidate Tlr4-expressing cells in the diabetic kidney include macrophages, podocytes and mesangial and tubular epithelial cells [8,9]. So far, we have been unable to obtain reliable findings by immunohistochemistry using commercially available antibodies for TLR4, and we are now trying other methods.…”

“…TLR4, one of the best-characterised TLRs, binds with lipopolysaccharide from Gram-negative bacterial cell walls and with several endogenous ligands [7]. TLR4 also plays an important role in various kidney disorders, such as glomerulonephritis, renal ischaemia and diabetic tubular inflammation [8][9][10][11][12][13], but the role of TLR4 in diabetic glomerular injury and hyperlipidaemia-induced kidney damage remains largely unknown.…”