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.
Glomerulonephritis can be exacerbated by infection. This study investigated the effect of N-palmitoyl-S-(2,3-bis(palmitoyloxy)-(2R,S)-propyl)-(R)-cysteinyl-seryl-(lysyl)3-lysine (Pam 3 CysSK 4 ), a synthetic Toll-like receptor 2 (TLR2) ligand, that was given at immunization on disease severity in accelerated nephrotoxic nephritis. Stimulation of TLR by microbial constituents is known to influence the development of the adaptive immunity. It was hypothesized that the TLR2 ligand Pam 3 CysSK 4 can modulate the development of disease in accelerated nephrotoxic nephritis by influencing the development of adaptive immunity. It is shown that Pam 3 CysSK 4 , when given at immunization, can increase profoundly the severity of disease, and with the use of TLR2-deficient mice, it is shown that this disease exacerbation depends on the presence of TLR2. Wild-type mice that were given Pam 3 CysSK 4 at immunization and had more severe disease also had a greater amount of antigen-specific IgG1, IgG2b, and IgG3 in the serum and more IgG2b and IgG3 deposited within the glomerulus. They also had increased numbers of glomerular CD4-positive T cells. Therefore, the more severe disease that was seen in the group that was immunized with lipopeptide can be attributed to an influence on the adaptive immune response.
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