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

Abstract

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.

Toll-Like Receptor 2 or Toll-Like Receptor 4 Deficiency Does Not Modify Lupus in MRLlpr Mice

“…More recently it has been shown that exogenously administered agonists of TLR3, TLR7 and TLR9 can exacerbate murine lupus [1], [2], [3], [4]. In addition several studies using the nephrotoxic nephritis model have shown a role for TLR2 and TLR4 through a number of mechanisms [5], [6], [7], [8]. Together these data support the idea that TLRs play a role in the exacerbation of lupus by bacterial and viral infection, as can be observed clinically.…”

The TLR4 antagonist CRX-526 protects against advanced diabetic nephropathy

“…Moreover, TLR4 expression in intrinsic renal cells and leukocytes has been reported to contribute to various acute and chronic kidney diseases. [27][28][29][30][31] The role of TLR4 in the pathogenesis of DN has been increasingly recognized. We and others have shown that TLR4 mediated high glucose-induced tubular inflammation, 19,32 and that the endogenous TLR4 ligand HMGB1 may have a role in TLR4 activation in DN.…”

Investigating mechanisms of chronic kidney disease in mouse models

“…Most published studies have focused on the phase of acute glomerular injury (which may be associated with impaired renal function in association with crescentic disease), while data on long-term follow-up to determine if the mice develop progressive tubulointerstitial fibrosis, tubular atrophy and renal insufficiency are sparse. Some studies have reported interstitial inflammation [59–61] and elevated serum creatinine levels but the latter are likely a consequence of severe glomerular damage [62, 63]. Our preliminary studies with NTS generated by the Shankland laboratory suggest that progressive tubulointerstitial disease requires repeated NTS injections [64].…”