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NLRP3 and ASC suppress lupus-like autoimmunity by driving the immunosuppressive effects of TGF-β receptor signalling
  1. Maciej Lech,
  2. Georg Lorenz,
  3. Onkar P Kulkarni,
  4. Marian O O Grosser,
  5. Nora Stigrot,
  6. Murthy N Darisipudi,
  7. Roman Günthner,
  8. Maximilian W M Wintergerst,
  9. David Anz,
  10. Heni Eka Susanti,
  11. Hans-Joachim Anders
  1. Medizinische Klinik und Poliklinik IV, Klinikum der Ludwig Maximilians Universität, München-Innenstadt, Munich, Germany
  1. Correspondence to Professor Hans-Joachim Anders, Medizinische Klinik und Poliklinik IV, Ludwig Maximilians Universität München, Ziemssenstr. 1, München 80336, Germany; hjanders{at}med.uni-muenchen.de

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.

  • Inflammation
  • Lupus Nephritis
  • Systemic Lupus Erythematosus

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