Key Points
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Toll-like receptors (TLRs), nucleotide-binding oligomerization domain receptors (NLRs) and the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome regulate inflammatory and repair processes in the kidneys
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TLRs prevent invasion and growth of pathogens in the urinary tract
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Inappropriate activation of TLRs, NLRs and the NLRP3 inflammasome is a major cause of acute and chronic kidney disease
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Gene-association studies have revealed connections between TLR gene mutations and the development of several inflammatory kidney disorders
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TLRs, NLRs and the NLRP3 inflammasome represent attractive novel drug targets to prevent and intervene in kidney inflammation and suppress immunopathology in kidney disease
Abstract
Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain receptors (NLRs) are families of pattern recognition receptors that, together with inflammasomes, sense and respond to highly conserved pathogen motifs and endogenous molecules released upon cell damage or stress. Evidence suggests that TLRs, NLRs and the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome have important roles in kidney diseases through regulation of inflammatory and tissue-repair responses to infection and injury. In this Review, we discuss the pathological mechanisms that are related to TLRs, NLRs and NLRP3 in various kidney diseases. In general, these receptors are protective in the host defence against urinary tract infection, but can sustain and self-perpetuate tissue damage in sterile inflammatory and immune-mediated kidney diseases. TLRs, NLRs and NLRP3, therefore, have become promising drug targets to enable specific modulation of kidney inflammation and suppression of immunopathology in kidney disease.
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References
Creagh, E. M. & O'Neill, L. A. TLRs, NLRs and RLRs: a trinity of pathogen sensors that co-operate in innate immunity. Trends Immunol. 27, 352–357 (2006).
Takeuchi, O. & Akira, S. Pattern recognition receptors and inflammation. Cell 140, 805–820 (2010).
Leemans, J. C., Cassel, S. L. & Sutterwala, F. S. Sensing damage by the NLRP3 inflammasome. Immunol. Rev. 243, 152–162 (2011).
Bryant, C. E. & Monie, T. P. Mice, men and the relatives: cross-species studies underpin innate immunity. Open Biol. 2, 120015 (2012).
Anders, H. J. Toll-like receptors and danger signaling in kidney injury. J. Am. Soc. Nephrol. 21, 1270–1274 (2010).
Beutler, B. Microbe sensing, positive feedback loops, and the pathogenesis of inflammatory diseases. Immunol. Rev. 227, 248–263 (2009).
Kawai, T. & Akira, S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat. Immunol. 11, 373–384 (2010).
Watters, T. M., Kenny, E. F. & O'Neill, L. Structure, function and regulation of the Toll/IL-1 receptor adaptor proteins. Immunol. Cell Biol. 85, 411–419 (2007).
O'Neill, L. A. & Bowie, A. G. The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nat. Rev. Immunol. 7, 353–364 (2007).
Ye, Z. & Ting, J. P. NLR, the nucleotide-binding domain leucine-rich repeat containing gene family. Curr. Opin. Immunol. 20, 3–9 (2008).
Carneiro, L. A., Magalhaes, J. G., Tattoli, I., Philpott, D. J. & Travassos, L. H. Nod-like proteins in inflammation and disease. J. Pathol. 214, 136–148 (2008).
Latz, E., Xiao, T. S. & Stutz, A. Activation and regulation of the inflammasomes. Nat. Rev. Immunol. 13, 397–411 (2013).
Wen, H., Miao, E. A. & Ting, J. P.-Y. Mechanisms of NOD-like receptor-associated inflammasome activation. Immunity 39, 432–441 (2013).
Anders, H. J. & Muruve, D. A. The inflammasomes in kidney disease. J. Am. Soc. Nephrol. 22, 1007–1018 (2011).
Iyer, S. S. et al. Mitochondrial cardiolipin is required for Nlrp3 inflammasome activation. Immunity 39, 311–323 (2013).
Zhou, R., Yazdi, A. S., Menu, P. & Tschopp, J. A role for mitochondria in NLRP3 inflammasome activation. Nature 469, 221–225 (2011).
Nakahira, K. et al. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat. Immunol. 12, 222–230 (2011).
Shimada, K. et al. Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity 36, 401–414 (2012).
Kayagaki, N. et al. Non-canonical inflammasome activation targets caspase-11. Nature 479, 117–121 (2011).
Lorenz, G., Darisipudi, M. N. & Anders, H.-J. Canonical and non-canonical effects of the NLRP3 inflammasome in kidney inflammation and fibrosis. Nephrol. Dial. Transplant. 41–48 (2013).
Ragnarsdóttir, B., Lutay, N., Gronberg-Hernandez, J., Köves, B. & Svanborg, C. Genetics of innate immunity and UTI susceptibility. Nat. Rev. Urol. 8, 449–468 (2011).
Fischer, H., Yamamoto, M., Akira, S., Beutler, B. & Svanborg, C. Mechanism of pathogen-specific TLR4 activation in the mucosa: fimbriae, recognition receptors and adaptor protein selection. Eur. J. Immunol. 36, 267–277 (2006).
Hagberg, L. et al. Difference in susceptibility to gram-negative urinary tract infection between C3H/HeJ and difference in susceptibility to gram-negative urinary tract infection between C3H/HeJ and C3H/HeN mice. Infect. Immun. 46, 839–844 (1984).
Hagberg, L., Briles, D. E. & Edén, C. S. Evidence for separate genetic defects in C3H/HeJ and C3HeB/FeJ mice, that affect susceptibility to gram-negative infections. J. Immunol. 134, 4118–4122 (1985).
Agace, W., Hedges, S. & Svanborg, C. Lps genotype in the C57 black mouse background and its influence on the interleukin-6 response to E. coli urinary tract infection. Scand. J. Immunol. 35, 531–538 (1992).
Leemans, J. C. et al. The toll interleukin-1 receptor (IL-1R) 8/single Ig domain IL-1R-related molecule modulates the renal response to bacterial infection. Infect. Immun. 80, 3812–3820 (2012).
Schilling, J. D., Martin, S. M., Hung., C. S., Lorenz, R. G. & Hultgren, S. J. Toll-like receptor 4 on stromal and hematopoietic cells mediates innate resistance to uropathogenic Escherichia coli. Proc. Natl Acad. Sci. USA 100, 4203–4208 (2003).
Patole, P. S. et al. Toll-like receptor-4: renal cells and bone marrow cells signal for neutrophil recruitment during pyelonephritis. Kidney Int. 68, 2582–2587 (2005).
Tsuboi, N. et al. Roles of toll-like receptors in C-C chemokine production by renal tubular epithelial cells. J. Immunol. 169, 2026–2033 (2002).
Chassin, C. et al. Renal collecting duct epithelial cells react to pyelonephritis-associated Escherichia coli by activating distinct TLR4-dependent and -independent inflammatory pathways. J. Immunol. 177, 4773–4784 (2006).
Good, D. W., George, T. & Watts, B. A. Lipopolysaccharide directly alters renal tubule transport through distinct TLR4-dependent pathways in basolateral and apical membranes. Am. J. Physiol. Ren. Physiol. 297, F866–F874 (2009).
Good, D. W., George, T. & Watts, B. A. Toll-like receptor 2 mediates inhibition of HCO3− absorption by bacterial lipoprotein in medullary thick ascending limb. Am. J. Physiol. Renal Physiol. 299, F536–F544 (2010).
Chassin, C. et al. TLR4 facilitates translocation of bacteria across renal collecting duct cells. J. Am. Soc. Nephrol. 19, 2364–2374 (2008).
Ragnarsdóttir, B. et al. Reduced toll-like receptor 4 expression in children with asymptomatic bacteriuria. J. Infect. Dis. 196, 475–484 (2007).
Yin, X. et al. Association of Toll-like receptor 4 gene polymorphism and expression with urinary tract infection types in adults. PLoS ONE 5, e14223 (2010).
Ragnarsdóttir, B. et al. Toll-like receptor 4 promoter polymorphisms: common TLR4 variants may protect against severe urinary tract infection. PLoS ONE 5, e10734 (2010).
Karoly, E. et al. Heat shock protein 72 (HSPA1B) gene polymorphism and Toll-like receptor (TLR) 4 mutation are associated with increased risk of urinary tract infection in children. Pediatr. Res. 61, 371–374 (2007).
Hawn, T. R. et al. Toll-like receptor polymorphisms and susceptibility to urinary tract infections in adult women. PLoS ONE 4, e5990 (2009).
Kau, A. L. et al. Enterococcus faecalis tropism for the kidneys in the urinary tract of C57BL/6J mice. Infect. Immun. 73, 2461–2468 (2005).
Yang, C.-W. et al. Toll-like receptor 2 mediates early inflammation by leptospiral outer membrane proteins in proximal tubule cells. Kidney Int. 69, 815–822 (2006).
Tabel, Y., Berdeli, A. & Mir, S. Association of TLR2 gene Arg753Gln polymorphism with urinary tract infection in children. Int. J. Immunogenet. 34, 399–405 (2007).
Hawn, T. R. et al. Genetic variation of the human urinary tract innate immune response and asymptomatic bacteriuria in women. PLoS ONE 4, e8300 (2009).
Cheng, C.-H., Lee, Y.-S., Chang, C.-J. & Lin, T.-Y. Genetic polymorphisms in Toll-like receptors among pediatric patients with renal parenchymal infections of different clinical severities. PLoS ONE 8, e58687 (2013).
Cheng, C.-H., Lee, Y.-S., Tsau, Y.-K. & Lin, T.-Y. Genetic polymorphisms and susceptibility to parenchymal renal infection among pediatric patients. Pediatr. Infect. Dis. J. 30, 309–314 (2011).
Andersen-Nissen, E. et al. Cutting edge: Tlr5−/− mice are more susceptible to Escherichia coli urinary tract infection. J. Immunol. 178, 4717–4720 (2007).
Zhang, D. et al. A toll-like receptor that prevents infection by uropathogenic bacteria. Science 303, 1522–1526 (2004).
Devarajan, P. Update on mechanisms of ischemic acute kidney injury. J. Am. Soc. Nephrol. 17, 1503–1520 (2006).
Chvojka, J. et al. New developments in septic acute kidney injury. Physiol. Res. 59, 859–869 (2010).
Miller, R. P., Tadagavadi, R. K., Ramesh, G. & Reeves, W. B. Mechanisms of cisplatin nephrotoxicity. Toxins (Basel). 2, 2490–518 (2010).
Lech, M. et al. Macrophage phenotype controls long-term AKI outcomes—kidney regeneration versus atrophy. J. Am. Soc. Nephrol. 25, 292–304 (2013).
Gonçalves, G. M., Castoldi, A., Braga, T. T. & Câmara, N. O. S. New roles for innate immune response in acute and chronic kidney injuries. Scand. J. Immunol. 73, 428–435 (2011).
Bonventre, J. V. & Zuk, A. Ischemic acute renal failure: an inflammatory disease? Kidney Int. 66, 480–485 (2004).
Mkaddem, S. B. et al. Heat shock protein gp96 interacts with protein phosphatase 5 and controls toll-like receptor 2 (TLR2)-mediated activation of extracellular signal-regulated kinase (ERK) 1/2 in post-hypoxic kidney cells. J. Biol. Chem. 284, 12541–12549 (2009).
Wu, H. et al. HMGB1 contributes to kidney ischemia reperfusion injury. J. Am. Soc. Nephrol. 21, 1878–1890 (2010).
Dessing, M. C. et al. RAGE does not contribute to renal injury and damage upon ischemia/reperfusion-induced injury. J. Innate. Immun. 4, 80–85 (2012).
Wu, H. et al. TLR4 activation mediates kidney ischemia/reperfusion injury. J. Clin. Invest. 117, 2847–2859 (2007).
Allam, R. et al. Histones from dying renal cells aggravate kidney injury via TLR2 and TLR4. J. Am. Soc. Nephrol. 23, 1375–1388 (2012).
Shah, N. et al. Prevention of acute kidney injury in a rodent model of cirrhosis following selective gut decontamination is associated with reduced renal TLR4 expression. J. Hepatol. 56, 1047–1053 (2012).
Wolfs, T. G. A. M. et al. In vivo expression of Toll-like receptor 2 and 4 by renal epithelial cells: IFN-γ and TNF-α mediated up-regulation during inflammation. J. Immunol. 168, 1286–1293 (2002).
Leemans, J. C. et al. Renal-associated TLR2 mediates ischemia/reperfusion injury in the kidney. J. Clin. Invest. 115, 2894–2903 (2005).
Pulskens, W. P. et al. Toll-like receptor-4 coordinates the innate immune response of the kidney to renal ischemia/reperfusion injury. PLoS ONE 3, e3596 (2008).
Chen, J. et al. Toll-like receptor 4 regulates early endothelial activation during ischemic acute kidney injury. Kidney Int. 79, 288–299 (2011).
Rusai, K. et al. Toll-like receptors 2 and 4 in renal ischemia/reperfusion injury. Pediatr. Nephrol. 25, 853–860 (2010).
Shigeoka, A. A. et al. TLR2 is constitutively expressed within the kidney and participates in ischemic renal injury through both MyD88-dependent and -independent pathways. J. Immunol. 178, 6252–6258 (2007).
Fukuzawa, N., Petro, M., Baldwin, W. M., Gudkov, A. V. & Fairchild, R. L. A TLR5 agonist inhibits acute renal ischemic failure. J. Immunol. 187, 3831–3839 (2011).
Li, X. et al. The role of Toll-like receptor (TLR) 2 and 9 in renal ischemia and reperfusion injury. Urology 81, 1379.e15–1379.e20 (2013).
Shigeoka, A. A. et al. Nod1 and nod2 are expressed in human and murine renal tubular epithelial cells and participate in renal ischemia reperfusion injury. J. Immunol. 184, 2297–2304 (2010).
Iyer, S. S. et al. Necrotic cells trigger a sterile inflammatory response through the Nlrp3 inflammasome. Proc. Natl Acad. Sci. USA 106, 20388–20393 (2009).
Shigeoka, A. A. et al. An inflammasome-independent role for epithelial-expressed Nlrp3 in renal ischemia-reperfusion injury. J. Immunol. 185, 6277–85 (2010).
Kim, H. J. et al. NLRP3 inflammasome knockout mice are protected against ischemic but not cisplatin-induced acute kidney injury. J. Pharmacol. Exp. Ther. 346, 465–472 (2013).
Melnikov, V. Y. et al. Impaired IL-18 processing protects caspase-1-deficient mice from ischemic acute renal failure. J. Clin. Invest. 107, 1145–1152 (2001).
Farrar, C. A. et al. Inhibition of TLR2 promotes graft function in a murine model of renal transplant ischemia-reperfusion injury. FASEB J. 26, 799–807 (2012).
Andrade-Oliveira, V. et al. TLR4 mRNA levels as tools to estimate risk for early posttransplantation kidney graft dysfunction. Transplantation 94, 589–595 (2012).
Krüger, B. et al. Donor Toll-like receptor 4 contributes to ischemia and reperfusion injury following human kidney transplantation. Proc. Natl Acad. Sci. USA 106, 3390–3395 (2009).
Krüger, B. et al. A comprehensive genotype-phenotype interaction of different Toll-like receptor variations in a renal transplant cohort. Clin. Sci. (Lond.). 119, 535–544 (2010).
Wu, H. et al. Absence of MyD88 signaling induces donor-specific kidney allograft tolerance. J. Am. Soc. Nephrol. 23, 1701–1716 (2012).
Dessing, M. C. et al. Intragraft Toll-like receptor profiling in acute renal allograft rejection. Nephrol. Dial. Transplant. 25, 4087–4092 (2010).
Ducloux, D. et al. Relevance of Toll-like receptor-4 polymorphisms in renal transplantation. Kidney Int. 67, 2454–2461 (2005).
Fekete, A. et al. Association between heat shock protein 70s and toll-like receptor polymorphisms with long-term renal allograft survival. Transplant. Int. 19, 190–196 (2006).
Palmer, S. M. et al. Donor polymorphisms in Toll-like receptor-4 influence the development of rejection after renal transplantation. Clin. Transplant. 20, 30–36 (2005).
Nogueira, E. et al. Incidence of donor and recipient toll-like receptor-4 polymorphisms in kidney transplantation. Transplant. Proc. 39, 412–414 (2007).
Eikmans, M. et al. The functional polymorphism Ala258Ser in the innate receptor gene ficolin-2 in the donor predicts improved renal transplant outcome. Transplantation 94, 478–485 (2012).
Cervera, C. et al. The influence of innate immunity gene receptors polymorphisms in renal transplant infections. Transplantation 83, 1493–1500 (2007).
Martins, G. A., Kawamura, M. T. & Carvalho, M. G. Detection of DNA in the plasma of septic patients. Ann. NY Acad. Sci. 906, 134–140 (2000).
Zhang, Q., Itagaki, K. & Hauser, C. J. Mitochondrial DNA is released by shock and activates neutrophils via p38 map kinase. Shock 34, 55–59 (2010).
Wang, H., Yang, H. & Tracey, K. J. Extracellular role of HMGB1 in inflammation and sepsis. J. Intern. Med. 255, 320–331 (2004).
El-Achkar, T. M. & Dagher, P. C. Renal Toll-like receptors: recent advances and implications for disease. Nat. Clin. Pract. Nephrol. 2, 568–581 (2006).
El-Achkar, T. M. et al. Sepsis induces changes in the expression and distribution of Toll-like receptor 4 in the rat kidney. Am. J. Physiol. Renal Physiol. 290, F1034–F1043 (2006).
Dear, J. W. et al. Sepsis-induced organ failure is mediated by different pathways in the kidney and liver: acute renal failure is dependent on MyD88 but not renal cell apoptosis. Kidney Int. 69, 832–836 (2006).
Castoldi, A. et al. TLR2, TLR4 and the MYD88 signaling pathway are crucial for neutrophil migration in acute kidney injury induced by sepsis. PLoS ONE 7, e37584 (2012).
Cunningham, P. N., Wang, Y., Guo, R., He, G. & Quigg, R. J. Role of Toll-like receptor 4 in endotoxin-induced acute renal failure. J. Immunol. 172, 2629–2635 (2004).
Yasuda, H. et al. Chloroquine and inhibition of Toll-like receptor 9 protect from sepsis-induced acute kidney injury. Am. J. Physiol. Renal Physiol. 294, F1050–F1058 (2008).
Scott, A. M. & Saleh, M. The inflammatory caspases: guardians against infections and sepsis. Cell Death Differ. 14, 23–31 (2007).
Brenmoehl, J. et al. Genetic variants in the NOD2/CARD15 gene are associated with early mortality in sepsis patients. Intensive Care Med. 33, 1541–1548 (2007).
Stroo, I. et al. Phenotyping of Nod1/2 double deficient mice and characterization of Nod1/2 in systemic inflammation and associated renal disease. Biol. Open 1, 1239–1247 (2012).
Zhang, B., Ramesh, G., Uematsu, S., Akira, S. & Reeves, W. B. TLR4 signaling mediates inflammation and tissue injury in nephrotoxicity. J. Am. Soc. Nephrol. 19, 923–932 (2008).
Sallustio, F. et al. Human renal stem/progenitor cells repair tubular epithelial cell injury through TLR2-driven inhibin-A and microvesicle-shuttled decorin. Kidney Int. 83, 392–403 (2013).
Sallustio, F. et al. TLR2 plays a role in the activation of human resident renal stem/progenitor cells. FASEB J. 24, 514–525 (2010).
Faubel, S. et al. Caspase-1-deficient mice are protected against cisplatin-induced apoptosis and acute tubular necrosis. Kidney Int. 66, 2202–2213 (2004).
Pulskens, W. P. et al. TLR4 promotes fibrosis but attenuates tubular damage in progressive renal injury. J. Am. Soc. Nephrol. 21, 1299–1308 (2010).
Pulskens, W. P. et al. Nlrp3 prevents early renal interstitial edema and vascular permeability in unilateral ureteral obstruction. PLoS ONE 9, e85775 (2014).
Leemans, J. C. et al. The role of Toll-like receptor 2 in inflammation and fibrosis during progressive renal injury. PLoS ONE 4, e5704 (2009).
Campbell, M. T. et al. Toll-like receptor 4: a novel signaling pathway during renal fibrogenesis. J. Surg. Res. 168, e61–e69 (2011).
Skuginna, V. et al. Toll-Like receptor signaling and SIGIRR in renal fibrosis upon unilateral ureteral obstruction. PLoS ONE 6, e19204 (2011).
Vilaysane, A. et al. The NLRP3 inflammasome promotes renal inflammation and contributes to CKD. J. Am. Soc. Nephrol. 21, 1732–1744 (2010).
Wang, W. et al. Inflammasome-independent NLRP3 augments TGF-β signaling in kidney epithelium. J. Immunol. 190, 1239–1249 (2013).
Babelova, A. et al. Biglycan, a danger signal that activates the NLRP3 inflammasome via toll-like and P2X receptors. J. Biol. Chem. 284, 24035–24048 (2009).
Lin, M. et al. Toll-like receptor 4 promotes tubular inflammation in diabetic nephropathy. J. Am. Soc. Nephrol. 23, 86–102 (2012).
Lin, M. et al. The TLR4 antagonist CRX-526 protects against advanced diabetic nephropathy. Kidney Int. 83, 887–900 (2013).
Kuwabara, T. et al. Exacerbation of diabetic nephropathy by hyperlipidaemia is mediated by Toll-like receptor 4 in mice. Diabetologia 55, 2256–2266 (2012).
Mudaliar, H. et al. The role of Toll-like receptor proteins (TLR) 2 and 4 in mediating inflammation in proximal tubules. Am. J. Physiol. Renal Physiol. 305, F143–F154 (2013).
Devaraj, S. et al. Knockout of toll-like receptor-2 attenuates both the proinflammatory state of diabetes and incipient diabetic nephropathy. Arterioscler. Thromb. Vasc. Biol. 31, 1796–804 (2011).
Kaur, H., Chien, A. & Jialal, I. Hyperglycemia induces Toll like receptor 4 expression and activity in mouse mesangial cells: relevance to diabetic nephropathy. Am. J. Physiol. Renal Physiol. 303, F1145–F1150 (2012).
Cha, J. J. et al. Renal protective effects of toll-like receptor 4 signaling blockade in type 2 diabetic mice. Endocrinology 154, 2144–2155 (2013).
Chen, K. et al. ATP-P2X4 signaling mediates NLRP3 inflammasome activation: a novel pathway of diabetic nephropathy. Int. J. Biochem. Cell Biol. 45, 932–943 (2013).
Wang, C., Pan, Y., Zhang, Q. Y., Wang, F. M. & Kong, L. D. Quercetin and allopurinol ameliorate kidney injury in STZ-treated rats with regulation of renal NLRP3 inflammasome activation and lipid accumulation. PLoS ONE 7, e38285 (2012).
Du, P. et al. NOD2 promotes renal injury by exacerbating inflammation and podocyte insulin resistance in diabetic nephropathy. Kidney Int. 84, 265–276 (2013).
Zhang, C. et al. Activation of Nod-like receptor protein 3 inflammasomes turns on podocyte injury and glomerular sclerosis in hyperhomocysteinemia. Hypertension 60, 154–162 (2012).
Hu, Q. H., Zhang, X., Pan, Y., Li, Y. C. & Kong, L. D. Allopurinol, quercetin and rutin ameliorate renal NLRP3 inflammasome activation and lipid accumulation in fructose-fed rats. Biochem. Pharmacol. 84, 113–125 (2012).
Bakker, P. J. et al. Nlrp3 is a key modulator of diet-induced nephropathy and renal cholesterol accumulation. Kidney Int. 85, 1112–1122 (2014).
Akahoshi, T., Murakami, Y. & Kitasato, H. Recent advances in crystal-induced acute inflammation. Curr. Opin. Rheumatol. 19, 146–150 (2007).
Kurts, C. A crystal-clear mechanism of chronic kidney disease. Kidney Int. 84, 859–861 (2013).
Mulay, S. R. et al. Calcium oxalate crystals induce renal inflammation by NLRP3-mediated IL-1β secretion. J. Clin. Invest. 123, 236–246 (2013).
Knauf, F. et al. NALP3-mediated inflammation is a principal cause of progressive renal failure in oxalate nephropathy. Kidney Int. 84, 895–901 (2013).
Anders, H. J. & Lech, M. NOD-like and Toll-like receptors or inflammasomes contribute to kidney disease in a canonical and a non-canonical manner. Kidney Int. 84, 225–228 (2013).
Mulay, S. R., Evan, A. & Anders, H. J. Molecular mechanisms of crystal-related kidney inflammation and injury. Implications for cholesterol embolism, crystalline nephropathies and kidney stone disease. Nephrol. Dial. Transplant. 29, 507–514 (2013).
Correa-Costa, M. et al. Pivotal role of Toll-like receptors 2 and 4, its adaptor molecule MyD88, and inflammasome complex in experimental tubule-interstitial nephritis. PLoS ONE 6, e29004 (2011).
Darisipudi, M. N. et al. Uromodulin triggers IL-1β-dependent innate immunity via the NLRP3 inflammasome. J. Am. Soc. Nephrol. 23, 1783–1789 (2012).
Saemann, M. D. et al. Tamm-Horsfall glycoprotein links innate immune cell activation with adaptive immunity via a Toll-like receptor-4-dependent mechanism. J. Clin. Invest. 115, 468–475 (2005).
Wang, S. et al. Recipient Toll-like receptors contribute to chronic graft dysfunction by both MyD88- and TRIF-dependent signaling. Dis. Model. Mech. 3, 92–103 (2010).
Lim, S. W. et al. Cyclosporine-induced renal injury induces toll-like receptor and maturation of dendritic cells. Transplantation 80, 691–699 (2005).
Braudeau, C. et al. Contrasted blood and intragraft toll-like receptor 4 mRNA profiles in operational tolerance versus chronic rejection in kidney transplant recipients. Transplantation 86, 130–136 (2008).
Christensen, S. R. et al. Toll-like receptor 9 controls anti-DNA autoantibody production in murine lupus. J. Exp. Med. 202, 321–331 (2005).
Marshak-Rothstein, A. & Rifkin, I. R. Immunologically active autoantigens: the role of toll-like receptors in the development of chronic inflammatory disease. Annu. Rev. Immunol. 25, 419–441 (2007).
Patole, P. S. et al. Expression and regulation of Toll-like receptors in lupus-like immune complex glomerulonephritis of MRL-Fas(lpr) mice. Nephrol. Dial. Transplant. 21, 3062–3073 (2006).
Wu, X. & Peng, S. L. Toll-like receptor 9 signaling protects against murine lupus. Arthritis Rheum. 54, 336–342 (2006).
Savarese, E. et al. Requirement of Toll-like receptor 7 for pristane-induced production of autoantibodies and development of murine lupus nephritis. Arthritis Rheum. 58, 1107–1115 (2008).
Lau, C. M. et al. RNA-associated autoantigens activate B cells by combined B cell antigen receptor/Toll-like receptor 7 engagement. J. Exp. Med. 202, 1171–1177 (2005).
Leadbetter, E. A. et al. Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature 416, 603–607 (2002).
Migliorini, A. & Anders, H. J. A novel pathogenetic concept-antiviral immunity in lupus nephritis. Nat. Rev. Nephrol. 8, 183–189 (2012).
Anders, H. J. et al. Activation of toll-like receptor-9 induces progression of renal disease in MRL-Fas(lpr) mice. FASEB J. 18, 534–536 (2004).
Pawar, R. D. et al. Toll-like receptor-7 modulates immune complex glomerulonephritis. J. Am. Soc. Nephrol. 17, 141–149 (2006).
Christensen, S. R. et al. Toll-like receptor 7 and TLR9 dictate autoantibody specificity and have opposing inflammatory and regulatory roles in a murine model of lupus. Immunity 25, 417–428 (2006).
Pawar, R. D. et al. Inhibition of Toll-like receptor-7 (TLR-7) or TLR-7 plus TLR-9 attenuates glomerulonephritis and lung injury in experimental lupus. J. Am. Soc. Nephrol. 18, 1721–1731 (2007).
Guiducci, C. et al. TLR recognition of self nucleic acids hampers glucocorticoid activity in lupus. Nature 465, 937–941 (2010).
Dong, L., Ito, S., Ishii, K. J. & Klinman, D. M. Suppressive oligodeoxynucleotides delay the onset of glomerulonephritis and prolong survival in lupus-prone NZB x NZW mice. Arthritis Rheum. 52, 651–658 (2005).
Lech, M. et al. IRF4 deficiency abrogates lupus nephritis despite enhancing systemic cytokine production. J. Am. Soc. Nephrol. 22, 1443–1452 (2011).
Lech, M. et al. Interleukin-1 receptor-associated kinase-M suppresses systemic lupus erythematosus. Ann. Rheum. Dis. 70, 2207–2217 (2011).
Lech, M. et al. Tir8/Sigirr prevents murine lupus by suppressing the immunostimulatory effects of lupus autoantigens. J. Exp. Med. 205, 1879–1888 (2008).
Kumagai, Y. et al. Cutting edge: TLR-dependent viral recognition along with type I IFN positive feedback signaling masks the requirement of viral replication for IFN-α production in plasmacytoid dendritic cells. J. Immunol. 182, 3960–3964 (2009).
Allam, R. et al. Viral 5'-triphosphate RNA and non-CpG DNA aggravate autoimmunity and lupus nephritis via distinct TLR-independent immune responses. Eur. J. Immunol. 38, 3487–3498 (2008).
Allam, R. et al. Viral RNA and DNA trigger common antiviral responses in mesangial cells. J. Am. Soc. Nephrol. 20, 1986–1996 (2009).
Suzuki, K., Imaizumi, T., Tsugawa, K., Ito, E. & Tanaka, H. Expression of retinoic acid-inducible gene-I in lupus nephritis. Nephrol. Dial. Transplant. 22, 2407–2409 (2007).
Patole, P. S. et al. Viral double-stranded RNA aggravates lupus nephritis through Toll-like receptor 3 on glomerular mesangial cells and antigen-presenting cells. J. Am. Soc. Nephrol. 16, 1326–1338 (2005).
Patole, P. S. et al. Coactivation of Toll-like receptor-3 and -7 in immune complex glomerulonephritis. J. Autoimmun. 29, 52–59 (2007).
Wornle, M. et al. Novel role of toll-like receptor 3 in hepatitis C-associated glomerulonephritis. Am. J. Pathol. 168, 370–385 (2006).
Fu, Y. et al. Innate stimuli accentuate end-organ damage by nephrotoxic antibodies via Fc receptor and TLR stimulation and IL-1/TNF-α production. J. Immunol. 176, 632–639 (2006).
Pawar, R. D. et al. Bacterial lipopeptide triggers massive albuminuria in murine lupus nephritis by activating Toll-like receptor 2 at the glomerular filtration barrier. Immunology 128, e206–e221 (2009).
Summers, S. A. et al. TLR9 and TLR4 are required for the development of autoimmunity and lupus nephritis in pristane nephropathy. J. Autoimmun. 35, 291–298 (2010).
Anders, H. J. et al. Bacterial CpG-DNA aggravates immune complex glomerulonephritis: role of TLR9-mediated expression of chemokines and chemokine receptors. J. Am. Soc. Nephrol. 14, 317–326 (2003).
Brown, H. J., Sacks, S. H. & Robson, M. G. Toll-like receptor 2 agonists exacerbate accelerated nephrotoxic nephritis. J. Am. Soc. Nephrol. 17, 1931–1939 (2006).
Suzuki, H. et al. Toll-like receptor 9 affects severity of IgA nephropathy. J. Am. Soc. Nephrol. 19, 2384–2395 (2008).
Coppo, R. et al. Toll-like receptor 4 expression is increased in circulating mononuclear cells of patients with immunoglobulin A nephropathy. Clin. Exp. Immunol. 159, 73–81 (2010).
Allam, R. & Anders, H. J. The role of innate immunity in autoimmune tissue injury. Curr. Opin. Rheumatol. 20, 538–544 (2008).
Lichtnekert, J. et al. Trif is not required for immune complex glomerulonephritis: dying cells activate mesangial cells via Tlr2/Myd88 rather than Tlr3/Trif. Am. J. Physiol. Renal Physiol. 296, 867–74 (2009).
Brown, H. J. et al. Toll-like receptor 4 ligation on intrinsic renal cells contributes to the induction of antibody-mediated glomerulonephritis via CXCL1 and CXCL2. J. Am. Soc. Nephrol. 18, 1732–1739 (2007).
Brown, H. J., Lock, H. R., Sacks, S. H. & Robson, M. G. TLR2 stimulation of intrinsic renal cells in the induction of immune-mediated glomerulonephritis. J. Immunol. 177, 1925–1931 (2006).
Machida, H. et al. Expression of Toll-like receptor 9 in renal podocytes in childhood-onset active and inactive lupus nephritis. Nephrol. Dial. Transplant. 25, 2530–2537 (2010).
Banas, M. C. et al. TLR4 links podocytes with the innate immune system to mediate glomerular injury. J. Am. Soc. Nephrol. 19, 704–713 (2008).
Kiberd, B. A. & Stadnyk, A. W. Established murine lupus nephritis does not respond to exogenous interleukin-1 receptor antagonist; a role for the endogenous molecule? Immunopharmacology 30, 131–137 (1995).
Reilly, M. et al. Randomized, double-blind, placebo-controlled, dose-escalating phase I, healthy subjects study of intravenous OPN-305, a humanized anti-TLR2 antibody. Clin. Pharmacol. Ther. 94, 593–600 (2013).
Hu, Y. M., Pai, M. H., Yeh, C. L., Hou, Y. C. & Yeh, S. L. Glutamine administration ameliorates sepsis-induced kidney injury by downregulating the high-mobility group box protein-1-mediated pathway in mice. Am. J. Physiol. Renal Physiol. 302, F150–F158 (2012).
Harrison, E. M. et al. Heat shock protein 90-binding agents protect renal cells from oxidative stress and reduce kidney ischemia-reperfusion injury. Am. J. Physiol. Renal Physiol. 295, F397–F405 (2008).
Packard, A. E. et al. Poly-IC preconditioning protects against cerebral and renal ischemia-reperfusion injury. J. Cereb. Blood Flow Metab. 32, 242–247 (2012).
Liu, M. et al. Protective effects of Toll-like receptor 4 inhibitor eritoran on renal ischemia-reperfusion injury. Transplant. Proc. 42, 1539–1544 (2010).
Opal, S. M. et al. Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: the ACCESS randomized trial. JAMA 309, 1154–1162 (2013).
Brumbaugh, A. R. & Mobley, H. L. T. Preventing urinary tract infection: progress toward an effective Escherichia coli vaccine. Expert Rev. Vaccines 11, 663–676 (2012).
Harberts, E. & Gaspari, A. A. TLR signaling and DNA repair: are they associated? J. Invest. Dermatol. 133, 296–302 (2013).
Rakoff-Nahoum, S. & Medzhitov, R. Role of toll-like receptors in tissue repair and tumorigenesis. Biochem. (Mosc.) 73, 555–561 (2008).
Kuo, M. C. et al. Ischemia-induced exocytosis of Weibel-Palade bodies mobilizes stem cells. J. Am. Soc. Nephrol. 19, 2321–2330 (2008).
Romagnani, P. & Anders, H.-J. What can tubular progenitor cultures teach us about kidney regeneration? Kidney Int. 83, 351–353 (2013).
Kim, B. S. et al. Ischemia-reperfusion injury activates innate immunity in rat kidneys. Transplantation 79, 1370–1377 (2005).
Bergler, T. et al. Toll-like receptor 4 in experimental kidney transplantation: early mediator of endogenous danger signals. Nephron Exp. Nephrol. 121, 59–70 (2012).
Benigni, A. et al. Involvement of renal tubular Toll-like receptor 9 in the development of tubulointerstitial injury in systemic lupus. Arthritis Rheum. 56, 1569–78 (2007).
Papadimitraki, E. D., Tzardi, M., Bertsias, G., Sotsiou, E. & Boumpas, D. T. Glomerular expression of toll-like receptor-9 in lupus nephritis but not in normal kidneys: implications for the amplification of the inflammatory response. Lupus 18, 831–835 (2009).
Lichtnekert, J. et al. Anti-GBM glomerulonephritis involves IL-1 but is independent of NLRP3/ASC inflammasome-mediated activation of caspase-1. PLoS ONE 6, e26778 (2011).
Tsai, P.-Y. et al. Epigallocatechin-3-gallate prevents lupus nephritis development in mice via enhancing the Nrf2 antioxidant pathway and inhibiting NLRP3 inflammasome activation. Free Radic. Biol. Med. 51, 744–754 (2011).
Acknowledgements
J.C.L. and L.K. have received support from the Netherlands Organization for Scientific Research (grant 016.126.386). J.C.L. is supported by the Dutch Kidney Foundation (grants C06.6023 and C10.2350) and H.-J.A. by the Deutsche Forschungsgemeinschaft (grants AN372/9-2 and AN327/14-1).
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Leemans, J., Kors, L., Anders, HJ. et al. Pattern recognition receptors and the inflammasome in kidney disease. Nat Rev Nephrol 10, 398–414 (2014). https://doi.org/10.1038/nrneph.2014.91
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DOI: https://doi.org/10.1038/nrneph.2014.91
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