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

Lech, Maciej; Lorenz, Georg; Kulkarni, Onkar P.; Grosser, Marian O. O.; Stigrot, Nora; Darisipudi, Murthy N.; Günthner, Roman; Wintergerst, Maximilian W. M.; Anz, David; Susanti, Heni Eka und Anders, Hans-Joachim (2015): NLRP3 and ASC suppress lupus-like autoimmunity by driving the immunosuppressive effects of TGF-beta receptor signalling. In: Annals of the rheumatic diseases, Vol. 74, No. 12: pp. 2224-2235

Abstract

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.

• Item Type: Journal article
• Form of publication: Publisher's Version
• Faculties: Medicine
• Subjects: 600 Technology > 610 Medicine and health
• ISSN: 1468-2060
• Alliance/National Licence: This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.
• Language: English