NLRP3 and ASC suppress lupus-like autoimmunity by driving the immunosuppressive effects of TGF-[beta] receptor signalling

• Published in: Annals of the rheumatic diseases Vol. 74; no. 12; p. 2224
• Main Authors: Lech, Maciej, Lorenz, Georg, Kulkarni, Onkar P, Grosser, Marian O O, Stigrot, Nora, Darisipudi, Murthy N, Gunthner, Roman, Wintergerst, Maximilian W M, Anz, David, Susanti, Heni Eka, Anders, Hans-Joachim
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group LTD 01.12.2015
• Subjects: Antigens; Apoptosis; Dendritic cells; Gene expression; Inflammation; Laboratories; Lung diseases; Lungs; Lupus; Lymphocytes; Neutrophils; Rodents; T cell receptors; California
• ISSN: 0003-4967; 1468-2060
• DOI: 10.1136/annrheumdis-2014-205496

Objectives 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.