NLRP3 and ASC suppress lupus-like autoimmunity by driving the immunosuppressive effects of TGF-β receptor signalling
NLRP3 and ASC suppress lupus-like autoimmunity by driving the immunosuppressive effects of TGF-β receptor signalling
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DOI：
10.1136/annrheumdis-2014-205496
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发表时间：
2015-12-01
影响因子：
27.4
通讯作者：
Anders, Hans-Joachim
中科院分区：
文献类型：
--
作者：
Lech, Maciej;Lorenz, Georg;Anders, Hans-Joachim
目的NLRP 3/ASC炎性小体通过激活caspase-1，触发成熟白细胞介素（IL）-1 β/IL-18的分泌，驱动宿主防御和自身炎症性疾病，但其在自身免疫中的潜在作用尚不明确。结果IL-1 R或IL-18的缺乏不影响C57 BL/6-lpr/lpr表型，而NLRP 3或ASC的缺乏在6个月内引发大量淋巴细胞增殖、肺T细胞浸润和严重的增生性狼疮肾炎，这些在年龄匹配的C57 BL/6-lpr/lpr对照中均不存在。NLRP 3或ASC的缺乏增加了树突状细胞和巨噬细胞的活化、多种促炎介质的表达、淋巴细胞坏死以及大多数T细胞和B细胞亚群的扩增。相反，浆细胞和自身抗体的产生几乎没有受到影响。NLRP 3和ASC的这种意想不到的免疫抑制作用可能与它们在肿瘤生长因子（TGF）-β受体信号传导过程中SMAD 2/3磷酸化中的已知作用有关，例如，在C57 BL/6-lpr/lpr小鼠中，Nlrp 3缺陷和Asc 3缺陷显著抑制了许多TGF-β靶基因的表达，并部分重现了已知的TGF-β 1-lpr/lpr小鼠的自身免疫表型。结论NLRP 3和ASC在自身免疫中具有非经典的免疫调节功能。
Objectives The NLRP3/ASC inflammasome drives host defence and autoinflammatory disorders by activating caspase-1 to trigger the secretion of mature interleukin (IL)-1 beta/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)-beta receptor signalling, for example, Nlrp3-deficiency and Asc-deficiency significantly suppressed the expression of numerous TGF-beta target genes in C57BL/6-lpr/lpr mice and partially recapitulated the known autoimmune phenotype of Tgf-beta 1-deficient mice.Conclusions These data identify a novel non-canonical immunoregulatory function of NLRP3 and ASC in autoimmunity.