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

A role for toll-like receptor 4 (TLR4) has been suggested in previous studies of glomerulonephritis, but the complex integration of these effects has not been explored. To separate effects on the innate and adaptive immune responses, we use the autologous nephrotoxic nephritis model with two disease induction protocols. First, we give a TLR4 ligand at the time of immunization and show the effects are mediated via TLR4 by comparing wild-type and TLR4-deficient mice. In wild-type mice histological measures of disease and serum creatinine are all at least twice as high as TLR4-deficient mice, due to an enhanced immune response to the nephritogenic sheep IgG. Second, we stimulate TLR4 later in the course of disease development and construct four groups of bone marrow chimeric or sham chimeric mice to study the role of TLR4 on bone marrow or renal cells. The most striking finding is that renal cell TLR4 stimulation increases glomerular crescent formation, with a mean of 21% and 25% in the two groups of mice with renal cell TLR4 compared with 0.1% and 0.6% in the two groups without, with differences mirrored by changes in serum creatinine. These findings, in a single disease model, illustrate that TLR4 stimulation triggers crescentic glomerulonephritis by effects on both the adaptive and innate immune response, with a crucial direct effect on renal cells. (Am J Pathol 2010, 177:644 653; DOI: 10.2353/ajpath.2010.091279)