title: The NLRP3/ASC inflammasome promotes T-cell-dependent immune complex glomerulonephritis by canonical and noncanonical mechanisms.
abstract: Interleukin (IL)-1β contributes to renal injury in immune complex glomerulonephritis. However, production of mature IL-1β depends on activation of the inflammasome that cleaves pro-IL-1β into its secretable form. A functional role of the NLRP3-containing inflammasome, which responds to various endogenous danger signals, was found in tubulointerstitial nephropathies, but its function in glomerular disease has not been established. To determine whether NLRP3 and its adapter molecule ASC contribute to glomerulonephritis, we induced T-cell-dependent autologous nephrotoxic serum nephritis in Nlrp3- and Asc-deficient mice. Renal expression of NLRP3/ASC inflammasome components and pro-IL-1β increased during nephrotoxic serum nephritis and was abundant in renal dendritic cells. This was associated with renal production of mature IL-1β, indicating inflammasome activation. Nlrp3 and Asc deficiency significantly attenuated glomerular injury, renal leukocyte infiltration, and T-cell activation. Production of mature IL-1β was abrogated in Asc-deficient mice, consistent with a loss of inflammasome-dependent IL-1β activation. Surprisingly, renal IL-1β secretion remained intact in Nlrp3-deficient mice, indicating noncanonical pro-inflammatory effects of NLRP3 in autologous nephrotoxic serum nephritis. This may include NLRP3-mediated glomerular release of pro-inflammatory high-mobility group box 1 protein as a noncanonical function of NLRP3/ASC in glomerulonephritis. Thus, therapeutic blockade of the NLRP3/ASC/IL-1β axis may be beneficial in glomerulonephritis.
authors.affiliation: Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Kirstin
authors.initials: K
authors.lastname: Andersen
authors.affiliation: Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Nuru
authors.initials: N
authors.lastname: Eltrich
authors.affiliation: Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Lichtnekert
authors.affiliation: Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Anders
authors.affiliation: Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Vielhauer
mesh_terms: D000419:Albuminuria / Q000276:immunology / Q000378:metabolism; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002634:Chemotaxis, Leukocyte; D005838:Genotype; D005921:Glomerulonephritis / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D024243:HMGB1 Protein / Q000378:metabolism; D007105:Immune Complex Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D058847:Inflammasomes / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D007668:Kidney / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008213:Lymphocyte Activation; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010641:Phenotype; D053573:Receptors, Interleukin-1 Type I / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D013997:Time Factors
chemical_list: D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; C587672:IL1B protein, mouse; C583355:IL1R1 protein, mouse; D058847:Inflammasomes; D018836:Inflammation Mediators; D053583:Interleukin-1beta; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C498534:Pycard protein, mouse; D053573:Receptors, Interleukin-1 Type I