title: NLRP3 and ASC suppress lupus-like autoimmunity by driving the immunosuppressive effects of TGF-β receptor signalling.
abstract: OBJECTIVE
  The NLRP3/ASC inflammasome drives host defence and autoinflammatory disorders by activating caspase-1 to trigger the secretion of mature interleukin (IL)-1β/IL-18, but its potential role in autoimmunity is speculative.
  
  
  METHODS
  We generated and phenotyped Nlrp3-deficient, Asc-deficient, Il-1r-deficient and Il-18-deficient C57BL/6-lpr/lpr mice, the latter being a mild model of spontaneous lupus-like autoimmunity.
  
  
  RESULTS
  While lack of IL-1R or IL-18 did not affect the C57BL/6-lpr/lpr phenotype, lack of NLRP3 or ASC triggered massive lymphoproliferation, lung T cell infiltrates and severe proliferative lupus nephritis within 6 months, which were all absent in age-matched C57BL/6-lpr/lpr controls. Lack of NLRP3 or ASC increased dendritic cell and macrophage activation, the expression of numerous proinflammatory mediators, lymphocyte necrosis and the expansion of most T cell and B cell subsets. In contrast, plasma cells and autoantibody production were hardly affected. This unexpected immunosuppressive effect of NLRP3 and ASC may relate to their known role in SMAD2/3 phosphorylation during tumour growth factor (TGF)-β receptor signalling, for example, Nlrp3-deficiency and Asc-deficiency significantly suppressed the expression of numerous TGF-β target genes in C57BL/6-lpr/lpr mice and partially recapitulated the known autoimmune phenotype of Tgf-β1-deficient mice.
  
  
  CONCLUSIONS
  These data identify a novel non-canonical immunoregulatory function of NLRP3 and ASC in autoimmunity.
authors.affiliation: Medizinische Klinik und Poliklinik IV, Klinikum der Ludwig Maximilians Universität, München-Innenstadt, Munich, Germany.
authors.forename: Maciej
authors.initials: M
authors.lastname: Lech
authors.affiliation: Medizinische Klinik und Poliklinik IV, Klinikum der Ludwig Maximilians Universität, München-Innenstadt, Munich, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Lorenz
authors.affiliation: Medizinische Klinik und Poliklinik IV, Klinikum der Ludwig Maximilians Universität, München-Innenstadt, Munich, Germany.
authors.forename: Onkar P
authors.initials: OP
authors.lastname: Kulkarni
authors.affiliation: Medizinische Klinik und Poliklinik IV, Klinikum der Ludwig Maximilians Universität, München-Innenstadt, Munich, Germany.
authors.forename: Marian O O
authors.initials: MO
authors.lastname: Grosser
authors.affiliation: Medizinische Klinik und Poliklinik IV, Klinikum der Ludwig Maximilians Universität, München-Innenstadt, Munich, Germany.
authors.forename: Nora
authors.initials: N
authors.lastname: Stigrot
authors.affiliation: Medizinische Klinik und Poliklinik IV, Klinikum der Ludwig Maximilians Universität, München-Innenstadt, Munich, Germany.
authors.forename: Murthy N
authors.initials: MN
authors.lastname: Darisipudi
authors.affiliation: Medizinische Klinik und Poliklinik IV, Klinikum der Ludwig Maximilians Universität, München-Innenstadt, Munich, Germany.
authors.forename: Roman
authors.initials: R
authors.lastname: Günthner
authors.affiliation: Medizinische Klinik und Poliklinik IV, Klinikum der Ludwig Maximilians Universität, München-Innenstadt, Munich, Germany.
authors.forename: Maximilian W M
authors.initials: MW
authors.lastname: Wintergerst
authors.affiliation: Medizinische Klinik und Poliklinik IV, Klinikum der Ludwig Maximilians Universität, München-Innenstadt, Munich, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Anz
authors.affiliation: Medizinische Klinik und Poliklinik IV, Klinikum der Ludwig Maximilians Universität, München-Innenstadt, Munich, Germany.
authors.forename: Heni Eka
authors.initials: HE
authors.lastname: Susanti
authors.affiliation: Medizinische Klinik und Poliklinik IV, Klinikum der Ludwig Maximilians Universität, München-Innenstadt, Munich, Germany.
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Anders
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000235:genetics*; D015551:Autoimmunity; D015153:Blotting, Western; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics*; D002478:Cells, Cultured; D004247:DNA / Q000235:genetics*; D005786:Gene Expression Regulation; D008181:Lupus Nephritis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C498534:Pycard protein, mouse; D004247:DNA
keywords: Inflammation; Lupus Nephritis; Systemic Lupus Erythematosus