TLR4 Links Podocytes with the Innate Immune System to Mediate Glomerular Injury

Abstract

Toll-like receptors (TLR) classically recognize pathogen-associated danger signals but are also activated via endogenous ligands. For evaluation of their role in inflammatory kidney disease, the function of TLR was analyzed in two mouse models of cryoglobulinemic membranoproliferative glomerulonephritis (MPGN; mice transgenic for thymic stromal lymphopoietin [TSLP], with or without deletion of the Fc␥ receptor IIb). Expression of TLR1 through 9 and TLR11 mRNA was detectable in whole kidneys and in isolated glomeruli of wild-type mice, with TLR3 and TLR4 having the highest absolute levels of expression. TLR1, 2, and 4 were increased in TSLP transgenic mice and even higher in TSLP transgenic Fc␥RIIb-deficient mice. TLR5 through 9 and 11 were upregulated to similar degrees in TSLP transgenic and TSLP transgenic Fc␥RIIb-deficient mice. Immunohistochemical studies of nephritic glomeruli localized TLR4 protein to podocytes. Cultured podocytes also expressed TLR4, and stimulation with TLR4-specific ligands resulted in a marked induction of chemokines; this was reduced by specific knockdown of TLR4 with siRNA. Fibrinogen, a potential endogenous TLR4 ligand, was shown to induce a similar profile of chemokines. In conclusion, it was demonstrated that TLR4 is constitutively expressed by podocytes and is upregulated in MPGN, where it may mediate glomerular injury by modulating expression of chemokines; therefore, TLR4 may link podocytes with the innate immune system to mediate MPGN triggered by the deposition of immune complexes.

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

“…More recently other investigators have detected protein with immunohistochemical staining for TLR4 reported to be on podocytes in normal mouse glomeruli. 21 Murine glomerular endothelial cells and podocytes both express TLR4, 22 and cultured podocytes have been shown to express TLR4 and to undergo phenotypic changes including cytoskeletal reorganization and B7.1 expression in response to TLR4 stimulation. 23 A further report demonstrated that podocytes express a range of chemokines in response to TLR4 stimulation.…”

“…23 A further report demonstrated that podocytes express a range of chemokines in response to TLR4 stimulation. 21 However, TLR4 has been localized to the glomerular endothelium rather than podocytes in frozen rat kidney, 24 and it seems likely that the findings would be the same in mice. Both Myd88 and TRIF dependent TLR4 signaling has been shown in murine mesangial cells, although TRIF deficient mice developed nephrotoxic nephritis to a similar degree to wild-type mice.…”

The Inflammasomes in Kidney Disease

“…This arm of the immune system involves several distinct families of soluble and cellular receptors that activate proinflammatory signaling pathways ( Figure 1). These cellular receptors include Toll-like receptors (TLRs), [1][2][3][4] retinoic acid-induced gene-like receptors, nucleotide-binding domain-leucine-rich repeat (or NOD-like receptors; NLRs), scavenger receptors, and C-type lectins that are activated by various bacterial and viral pathogen-associated molecular patterns (PAMPs), resulting the engagement of nuclear factor-B (NF-B), 5 IFN regulatory factors, and mitogen-activated protein kinase signaling pathways modulating proinflammatory and type I IFN genes.…”

Immune system in renal injury and repair: Burning the candle from both ends?

“…These authors fed TLR4 knockout and control mice a high fat diet, observed protection of TLR4 −/− mice, and were able to demonstrate that TLR4 in adipocytes and macrophages was activated by fatty acids, thus contributing to pro-inflammatory signaling and development of insulin resistance in these obese mice. In two mouse models of cryoglobulinemic membranoproliferative glomerulonephritis, TLR3 and TLR4 expression was significantly increased, with TLR4 localized to nephritic podocytes where it may regulate production of inflammatory cytokines and contribute to immunemediated injury (49). In a mouse model of acute renal ischemia, injury was much attenuated in TLR2 −/− mice (50).…”