TLR2 Stimulation of Intrinsic Renal Cells in the Induction of Immune-Mediated Glomerulonephritis

Brown, Heather J.; Lock, Helen R.; Sacks, Steven H.; Robson, Michael G.

doi:10.4049/jimmunol.177.3.1925

Cited by 58 publications

(33 citation statements)

References 32 publications

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“…Early reports showed that a small dose of endotoxin could exacerbate the heterologous phase in the rat [17]. Our own studies extended these findings using specific ligands for TLR2 or TLR4, given with glomerular binding antibody [3, 4]. Bone marrow chimera experiments showed that there was an important role for TLR2 or TLR4 on renal cells in addition to neutrophils.…”

Section: Introductionsupporting

confidence: 63%

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Toll-Like Receptors and Renal Disease

Robson

2009

Nephron Exp Nephrol

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Toll-like receptors (TLRs) play a central role in the response of both the innate and the adaptive immune system to microbial ligands. There is also evidence that they are stimulated by endogenous ligands. In this review, I discuss evidence that they are important in renal disease. This discussion considers the role of both endogenous and microbial ligands, and also the contribution of TLRs present on leucocytes and on intrinsic renal cells. There is strong evidence of a role for TLR2 and TLR4 in renal ischaemia-reperfusion injury, with the effects probably mediated by endogenous ligands. In systemic lupus erythematosus, stimulation of TLR7 and TLR9 by host-derived nucleic acids is important. TLR7 stimulation exacerbates disease, but the role of TLR9 is complex. I also discuss evidence that they are important in other forms of glomerulonephritis, with evidence derived mainly from experimental models in which exogenous ligands have been administered.

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Section: Introductionsupporting

confidence: 63%

“…Primary cultures of mouse renal tubular epithelial cells express TLR1–TLR4 and TLR6 [1]. Cultured mouse mesangial cells show this same pattern of TLR expression [2,3,4]. These studies on cultured cells are of value, but of more interest is TLR expression in vivo, as demonstrated on intact tissue sections.…”

Section: Introductionmentioning

confidence: 99%

Toll-Like Receptors and Renal Disease

Robson

2009

Nephron Exp Nephrol

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“…Still, glomerular inflammation in heterologous anti-GBM disease involves innate rather than adaptive immunity given that the model was MyD88- but not Rag2-dependent. Since injury in this model was previously shown to involve TLR2 and TLR4 [33], [34] we assume that the TLR2/MyD88 and the TLR4/MyD88 pathways predominate for the induction of innate immunity in this model of acute glomerulonephritis.…”

Section: Discussionmentioning

confidence: 98%

Anti-GBM Glomerulonephritis Involves IL-1 but Is Independent of NLRP3/ASC Inflammasome-Mediated Activation of Caspase-1

Lichtnekert¹,

Kulkarni²,

Mulay³

et al. 2011

PLoS ONE

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IL-1β and IL-18 are proinflammatory cytokines that contribute to renal immune complex disease, but whether IL-1β and IL-18 are mediators of intrinsic glomerular inflammation is unknown. In contrast to other cytokines the secretion of IL-1β and IL-18 requires a second stimulus that activates the inflammasome-ASC-caspase-1 pathway to cleave pro-IL-1β and -IL-18 into their mature and secretable forms. As the NLRP3 inflammasome and caspase-1 were shown to contribute to postischemic and postobstructive tubulointerstitial inflammation, we hypothesized a similar role for NLRP3, ASC, and caspase-1 in glomerular immunopathology. This concept was supported by the finding that lack of IL-1R1 reduced antiserum-induced focal segmental necrosis, crescent formation, and tubular atrophy when compared to wildtype mice. Lack of IL-18 reduced tubular atrophy only. However, NLRP3-, ASC- or caspase-1-deficiency had no significant effect on renal histopathology or proteinuria of serum nephritis. In vitro studies with mouse glomeruli or mesangial cells, glomerular endothelial cells, and podocytes did not reveal any pro-IL-1β induction upon LPS stimulation and no caspase-1 activation after an additional exposure to the NLRP3 agonist ATP. Only renal dendritic cells, which reside mainly in the tubulointerstitium, expressed pro-IL-1β and were able to activate the NLRP3-caspase-1 axis and secrete mature IL-1β. Together, the NLRP3-ASC-caspase-1 axis does not contribute to intrinsic glomerular inflammation via glomerular parenchymal cells as these cannot produce IL-1β during sterile inflammation.

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“…Both have been shown to affect the course of glomerulonephritis, although these studies involved exogenous administration of ligands [23,24]. Both TLR2 and TLR4 have also been shown to mediate renal injury following ischaemia/reperfusion [25,26,27].…”

Section: Discussionmentioning

confidence: 99%

Endogenous Ligands for TLR2 and TLR4 Are Not Involved in Renal Injury following Ureteric Obstruction

Chowdhury

Sacks

Sheerin

2010

Nephron Exp Nephrol

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Background: Toll-like receptors (TLRs) are a recently described arm of innate immunity. As well as responding to conserved molecular patterns found on pathogens, TLRs can also respond to endogenous ligands. Those described for TLR2 and TLR4 include molecules released following tissue injury including heat shock proteins and matrix proteins. We hypothesised that following injury, TLRs on renal tubular cells are activated by these endogenous ligands, resulting in cytokine production and cellular infiltration which propagate the fibrotic process. Methods: We performed unilateral ureteric obstruction (UUO) in wild-type C57BL/6, TLR2 knockout and TLR4 knockout mice. Gene expression of TGF-β and TNF-α within renal tissue was analysed by real-time PCR. Kidneys were also scored for the level of tubulointerstitial fibrosis, collagen type IV deposition and macrophage infiltration. Results: No significant difference was found in the degree of tubulointerstitial fibrosis, collagen type IV deposition or macrophage infiltration 14 days after UUO between the 3 groups. Renal TNF-α and TGF-β gene expression was also similar in all groups 3 days after UUO. Conclusions: TLR2 and TLR4 do not play a significant role in the development of tubulointerstitial fibrosis following obstruction.

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TLR2 Stimulation of Intrinsic Renal Cells in the Induction of Immune-Mediated Glomerulonephritis

Cited by 58 publications

References 32 publications

Toll-Like Receptors and Renal Disease

Toll-Like Receptors and Renal Disease

Anti-GBM Glomerulonephritis Involves IL-1 but Is Independent of NLRP3/ASC Inflammasome-Mediated Activation of Caspase-1

Endogenous Ligands for TLR2 and TLR4 Are Not Involved in Renal Injury following Ureteric Obstruction

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