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A crystal-clear mechanism of chronic kidney disease

2013; Elsevier BV; Volume: 84; Issue: 5 Linguagem: Inglês

10.1038/ki.2013.251

1523-1755

Christian Kurts,

Trace Elements in Health

Knauf et al. demonstrate that prolonged activation of the intrarenal inflammasome is responsible for the loss of kidney function in oxalate crystal nephropathy. These findings suggest new therapeutic opportunities for patients suffering from severe hereditary kidney diseases such as primary hyperoxaluria, and reveal a previously unappreciated general mechanism of kidney disease progression that may also contribute to conditions other than crystal nephropathy. Knauf et al. demonstrate that prolonged activation of the intrarenal inflammasome is responsible for the loss of kidney function in oxalate crystal nephropathy. These findings suggest new therapeutic opportunities for patients suffering from severe hereditary kidney diseases such as primary hyperoxaluria, and reveal a previously unappreciated general mechanism of kidney disease progression that may also contribute to conditions other than crystal nephropathy. The defense against pathogens and the repair of tissue damage by the immune system require the ability to sense injury in the first place. This function is performed by several families of innate immune signaling receptors that activate the cells of our body and induce distinct transcriptional programs for inflammation and/or anti-infectious defense. These receptors respond to molecules uniquely found in microbes, or to host molecules that either appear in non-physiological locations or are chemically altered during tissue damage. Widely studied examples include the members of the Toll-like receptor (TLR) family and the Rig-I-like helicases. Recent research has uncovered the important roles of the members of the nucleotide-binding domain leucine-rich repeat-containing (NLR) families in pattern sensing.1.Gross O. Thomas C.J. Guarda G. et al.The inflammasome: an integrated view.Immunol Rev. 2011; 243: 136-151Crossref PubMed Scopus (583) Google Scholar NLR proteins assemble large molecular structures in the cytosol by self-oligomerization—the inflammasomes.1.Gross O. Thomas C.J. Guarda G. et al.The inflammasome: an integrated view.Immunol Rev. 2011; 243: 136-151Crossref PubMed Scopus (583) Google Scholar These function as enzymatic complexes that proteolytically activate key proinflammatory cytokines, especially interleukin-1 (IL-1). The central importance of IL-1 in innate immunity is evidenced by the efficacy of IL-1 inhibitors such as anakinra in the treatment of many types of sterile inflammation.2.Dinarello C.A. IL-1: discoveries, controversies and future directions.Eur J Immunol. 2010; 40: 599-606Crossref PubMed Scopus (191) Google Scholar The best-studied inflammasome is assembled by the NLRP3 protein, also known as cryopyrin.3.Latz E. The inflammasomes: mechanisms of activation and function.Curr Opin Immunol. 2010; 22: 28-33Crossref PubMed Scopus (355) Google Scholar This protein is composed of three domains (Figure 1): first, a C-terminal leucine-rich repeat domain that mediates pattern recognition; second, an intermediate nucleotide-binding and oligomerization domain that facilitates the self-oligomerization; and third, an N-terminal pyrin, which interacts with pyrin-containing downstream signaling intermediates, such as apoptosis-associated speck-like protein containing a carboxy-terminal CARD (ASC). The caspase activation and recruitment domain (CARD) in ASC can activate caspase-1, which activates IL-1 and IL-18 by proteolysis, thereby inducing potent inflammatory responses. Several gain-of-function mutants of NLRP3 have been described that cause severe autoinflammatory diseases, such as Muckle–Wells syndrome.1.Gross O. Thomas C.J. Guarda G. et al.The inflammasome: an integrated view.Immunol Rev. 2011; 243: 136-151Crossref PubMed Scopus (583) Google Scholar,3.Latz E. The inflammasomes: mechanisms of activation and function.Curr Opin Immunol. 2010; 22: 28-33Crossref PubMed Scopus (355) Google Scholar Various triggers of the NLRP3 inflammasome with different physical properties and chemical compositions have been described. These include microbial stimuli (viruses, bacteria, protozoans, and fungi) and crystalline or aggregated substances such as amyloid, pore-forming toxins, or necrotic cell components.1.Gross O. Thomas C.J. Guarda G. et al.The inflammasome: an integrated view.Immunol Rev. 2011; 243: 136-151Crossref PubMed Scopus (583) Google Scholar, 3.Latz E. The inflammasomes: mechanisms of activation and function.Curr Opin Immunol. 2010; 22: 28-33Crossref PubMed Scopus (355) Google Scholar, 4.Anders H.J. Muruve D.A. The inflammasomes in kidney disease.J Am Soc Nephrol. 2011; 22: 1007-1018Crossref PubMed Scopus (283) Google Scholar The exact mechanisms that allow inflammasome assembly by such a diverse array of substances are still unclear. It has been suggested that these substances initiate the production of common intermediates that are recognized directly or indirectly by NLRP3, such as reactive oxygen species. Alternatively, there is evidence that many, especially crystalline, NLRP3 inflammasome activators function by mechanically damaging lysosome membranes. The resulting release of lysosomal proteases such as cathepsins into the cytosol may activate NLRP3 directly or indirectly.1.Gross O. Thomas C.J. Guarda G. et al.The inflammasome: an integrated view.Immunol Rev. 2011; 243: 136-151Crossref PubMed Scopus (583) Google Scholar In addition to these triggers, MyD88 signaling, for instance through Toll-like receptors, is required for NLRP3 activation, as well as the presence of intracellular adenosine triphosphate. Although the exact molecular mechanisms of NLRP3 activation are still under intense investigation, the clinical importance of the inflammasome in anti-infectious innate immunity on the one hand,5.Muruve D.A. Petrilli V. Zaiss A.K. et al.The inflammasome recognizes cytosolic microbial and host DNA and triggers an innate immune response.Nature. 2008; 452: 103-107Crossref PubMed Scopus (756) Google Scholar and in sterile inflammation on the other hand, is widely appreciated. Especially, the ability of various crystals to activate the NLRP3 inflammasome has raised considerable interest in recent years, because it shed new light on the pathomechanisms of many important diseases. For example, inflammation in gout and vessel inflammation in arteriosclerosis result from NLRP3 inflammasome activation by uric acid crystals and cholesterol crystals, respectively, and asbestos and silica crystals use this inflammasome to induce sterile lung inflammation.1.Gross O. Thomas C.J. Guarda G. et al.The inflammasome: an integrated view.Immunol Rev. 2011; 243: 136-151Crossref PubMed Scopus (583) Google Scholar,3.Latz E. The inflammasomes: mechanisms of activation and function.Curr Opin Immunol. 2010; 22: 28-33Crossref PubMed Scopus (355) Google Scholar The inflammasome is involved also in renal disease, as first demonstrated by the attenuation of obstructive uropathy in NLRP3-deficient mice.6.Vilaysane A. Chun J. Seamone M.E. et al.The NLRP3 inflammasome promotes renal inflammation and contributes to CKD.J Am Soc Nephrol. 2010; 21: 1732-1744Crossref PubMed Scopus (389) Google Scholar However, a role of the inflammasome in crystal nephropathy was demonstrated only recently, first by Mulay et al.7.Mulay S.R. Kulkarni O.P. Rupanagudi K.V. et al.Calcium oxalate crystals induce renal inflammation by NLRP3-mediated IL-1β secretion.J Clin Invest. 2013; 123: 236-246Crossref PubMed Scopus (311) Google Scholar from the Anders group in Munich. These authors used a mouse model of crystal nephropathy induced by feeding with an oxalate-rich diet, which causes tubular precipitation of calcium oxalate.8.Khan S.R. Crystal-induced inflammation of the kidneys: results from human studies, animal models, and tissue-culture studies.Clin Exp Nephrol. 2004; 8: 75-88Crossref PubMed Scopus (226) Google Scholar Standard pathophysiological concepts assumed that oxalate nephropathy mechanically damages the kidney as a consequence of tubular obstruction by the crystals. Although such obstruction certainly occurs, it cannot explain the molecular mechanisms underlying the ensuing sterile kidney inflammation. Mulay et al. discovered that inflammasome activation by oxalate crystals provides the link to sterile inflammation. In hindsight, the involvement of the inflammasome in oxalate nephropathy appears plausible, given that the high osmolarity in certain renal segments, especially in the medulla, predisposes this organ to crystal formation. Mulay et al. went on to clarify the precise molecular mechanisms, by demonstrating the requirement of NLRP3, MyD88, caspase-1, IL-1, IL-1R, and ASC with the use of the respective knockout mice. Moreover, they identified the cell in which inflammasome activation took place as the dendritic cell of the kidney. These resident immune cells form an intricate network in the renal interstitium and serve sentinel functions, for example against ischemic or obstructive kidney injury or bacterial infections.9.Teteris S.A. Engel D.R. Kurts C. Homeostatic and pathogenic role of renal dendritic cells.Kidney Int. 2011; 80: 139-145Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar Sensing intrarenal crystal precipitation now emerges as a new function of these cells. Mulay et al. finally showed that conditional depletion of dendritic cells, pharmacological inhibition of IL-1, or the application of drugs that induce intracellular adenosine triphosphate degradation attenuates sterile inflammation in the kidney.7.Mulay S.R. Kulkarni O.P. Rupanagudi K.V. et al.Calcium oxalate crystals induce renal inflammation by NLRP3-mediated IL-1β secretion.J Clin Invest. 2013; 123: 236-246Crossref PubMed Scopus (311) Google Scholar These findings elegantly extrapolated the basic immunological discoveries described above into preclinical application. However, the model used by Mulay et al. allowed examination only of acute renal injury, as kidney function quickly recovered after a few days. Thus, the consequences of crystal formation and inflammasome activation for chronic kidney disease remained unclear. This important question has now been answered by Knauf et al.10.Knauf F. Asplin J.R. Granja I. et al.NALP3-mediated inflammation is a principal cause of progressive renal failure in oxalate nephropathy.Kidney Int. 2013; 84: 895-901Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar (this issue) from the Aronson group at Yale. These authors managed to modify the oxalate feeding protocol so that it could be maintained over up to 30 days. After only 1 week of feeding mice a diet high in oxalate, they observed crystal precipitation and serious tubulointerstitial infiltration and inflammation and, importantly, a sustained reduction of kidney function. Adding calcium to the diet prevented these symptoms by forming calcium oxalate in the intestinal lumen, thereby reducing oxalate resorption. In NALP3 knockout mice, crystal formation in the kidney still occurred, but inflammasome activation, mononuclear infiltration, and renal failure were potently inhibited. These findings allowed the conclusion that NALP3-mediated inflammasome activation also drives progressive renal failure in oxalate nephropathy (Figure 1).10.Knauf F. Asplin J.R. Granja I. et al.NALP3-mediated inflammation is a principal cause of progressive renal failure in oxalate nephropathy.Kidney Int. 2013; 84: 895-901Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar This extension is important, as it supports the notion that inflammasome activation drives chronic kidney disease, especially in hereditary forms of crystal nephropathies. Among the most important of these diseases are the different forms of primary hyperoxaluria, which can lead to terminal kidney failure in early life.11.Hoppe B. An update on primary hyperoxaluria.Nat Rev Nephrol. 2012; 8: 467-475Crossref PubMed Scopus (188) Google Scholar These conditions arise from several genetic defects in liver cells, for instance of alanine-glyoxylate-aminotransferase or of glyoxylate reductase, and result in increased production or reduced metabolization of oxalate. In contrast to uncomplicated kidney stone disease, which can often be treated simply by more fluid intake and by dietary measures, therapy of these hereditary diseases is difficult. Terminal kidney failure is often unavoidable, and tends to recur after kidney transplantation. Although inflammasome inhibition clearly is not a causal therapy for these diseases, it may at least slow their progression, by preventing the crystal-induced inflammation that leads to kidney failure.11.Hoppe B. An update on primary hyperoxaluria.Nat Rev Nephrol. 2012; 8: 467-475Crossref PubMed Scopus (188) Google Scholar There are mouse models for primary hyperoxaluria, in which the genes affected in patients are incapacitated, and which may better mimic the high oxalate burden in these patients. An important future step will be to inhibit the inflammasome or IL-1 in these mouse models, to ascertain the benefit that can be expected from these measures in hereditary forms of hyperoxaluria. Finally, the groundbreaking studies by Mulay et al.7.Mulay S.R. Kulkarni O.P. Rupanagudi K.V. et al.Calcium oxalate crystals induce renal inflammation by NLRP3-mediated IL-1β secretion.J Clin Invest. 2013; 123: 236-246Crossref PubMed Scopus (311) Google Scholar and Knauf et al.10.Knauf F. Asplin J.R. Granja I. et al.NALP3-mediated inflammation is a principal cause of progressive renal failure in oxalate nephropathy.Kidney Int. 2013; 84: 895-901Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar identify a previously unknown fundamental mechanism for progression of chronic kidney disease: inflammasome activation in kidney dendritic cells, which causes IL-1-mediated sterile inflammation, kidney fibrosis, and renal failure. This mechanism may likely contribute also to other forms of chronic kidney disease associated with crystal formation, such as gout nephropathy. The unexpected role of inflammasome inactivation by protein aggregates in type 2 diabetes, adult macula degeneration, and Alzheimer’s disease1.Gross O. Thomas C.J. Guarda G. et al.The inflammasome: an integrated view.Immunol Rev. 2011; 243: 136-151Crossref PubMed Scopus (583) Google Scholar, 3.Latz E. The inflammasomes: mechanisms of activation and function.Curr Opin Immunol. 2010; 22: 28-33Crossref PubMed Scopus (355) Google Scholar, 4.Anders H.J. Muruve D.A. The inflammasomes in kidney disease.J Am Soc Nephrol. 2011; 22: 1007-1018Crossref PubMed Scopus (283) Google Scholar raises the possibility that this mechanism may contribute also to degenerative kidney diseases in which such deposits are observed. Thus, uromodulin has recently been described as a protein-aggregate-like inflammasome activator,12.Darisipudi M.N. Thomasova D. Mulay S.R. et al.Uromodulin triggers IL-1β-dependent innate immunity via the NLRP3 inflammasome.J Am Soc Nephrol. 2012; 23: 1783-1789Crossref PubMed Scopus (110) Google Scholar and amyloid composed of β2-microglobulin is another likely candidate. Future studies may hold more surprising discoveries in store. Clinical studies will show whether and to what extent inflammasome inhibition can improve therapy of chronic kidney disease.