NLRP3 and ASC suppress lupus-like autoimmunity by driving the immunosuppressive effects of TGF-ß receptor signalling.
Ann Rheum Dis
; 74(12): 2224-35, 2015 Dec.
Article
in En
| MEDLINE
| ID: mdl-25135254
ABSTRACT
OBJECTIVES:
The NLRP3/ASC inflammasome drives host defence and autoinflammatory disorders by activating caspase-1 to trigger the secretion of mature interleukin (IL)-1ß/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 6â 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)-ß receptor signalling, for example, Nlrp3-deficiency and Asc-deficiency significantly suppressed the expression of numerous TGF-ß target genes in C57BL/6-lpr/lpr mice and partially recapitulated the known autoimmune phenotype of Tgf-ß1-deficient mice.CONCLUSIONS:
These data identify a novel non-canonical immunoregulatory function of NLRP3 and ASC in autoimmunity.Key words
Full text:
1
Database:
MEDLINE
Main subject:
Lupus Nephritis
/
DNA
/
Carrier Proteins
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Autoimmunity
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Gene Expression Regulation
/
Apoptosis Regulatory Proteins
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Ann Rheum Dis
Year:
2015
Type:
Article
Affiliation country:
Germany