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

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.

Deficient NLRP3 and AIM2 Inflammasome Function in Autoimmune NZB Mice

“…Interestingly, recent work on another lupus model demonstrated that NLRP3 protected against disease development (34). Contrary to their hypothesis that NLRP3 would contribute to disease in C57BL/6 mice with a Fas lpr mutation, the authors found exacerbated pathology upon deletion of the genes for either NLRP3 or ASC.…”

“…Earlier published work implicated NLRP3 in kidney damage in various scenarios, including lupus (30,31,61), and from this work it would be reasonable to propose that the lack of NLRP3 in NZB protects them from kidney pathology seen in the NZB3NZW F1 mice. The contradictory results of Lech et al (34) suggest that such assumptions on the role of NLRP3 require testing in this model. Interestingly, type I IFN, which is commonly chronically elevated in SLE, antagonizes NLRP3 inflammasome function (62).…”

“…Thus, inflammasome function promoted disease in this model, but because elevated IL-1b is not typical of human lupus, the relevance of this to the initiation of the majority of SLE is uncertain. In contrast, deletion of NLRP3 or ASC from a mild spontaneous model of SLE (Fas lpr mutation on C57BL/6 background) causes exacerbated disease (34). Thus, the role of inflammasomes in lupus-like autoimmunity remains uncertain.…”

Of Inflammasomes and Alarmins: IL-1β and IL-1α in Kidney Disease

“…87 However, in lupus nephritis of C57BL/6-(Fas)lpr mice lack of NLRP3 and ASC consistently presented an aggravated phenotype. 48 As the same was not found for lack of IL-1R or IL-18 an inflammasome-independent effect was postulated. 48 For example, NLPR3 and ASC mediate TGFR-dependent SMAD phosphorylation, 48 a signaling pathway known to suppress lupus nephritis via the known immunoregulatory effects of TGF-b signaling on autoimmunity.…”

“…46,47 Finally, several studies suggest that NLRP3 and ASC have other, inflammasomeindependent biologic functions, such as facilitating the anti-inflammatory and profibrotic effects of TGF-bR signaling. 48,49 …”