Lack of SIGIRR/TIR8 aggravates hydrocarbon oil-induced lupus nephritis
Lack of SIGIRR/TIR8 aggravates hydrocarbon oil-induced lupus nephritis
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DOI：
10.1002/path.2678
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发表时间：
2010-04-01
影响因子：
7.3
通讯作者：
Anders, Hans-Joachim
中科院分区：
文献类型：
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作者：
Lech, Maciej;Skuginna, Veronika;Anders, Hans-Joachim
多种遗传因素导致自发性系统性红斑狼疮(SLE)的临床变异，但它们在药物诱导的SLE中的作用仍很大程度上尚不清楚。烃类油诱导的系统性红斑狼疮依赖于间皮细胞的凋亡和Toll样受体(TLR)-7介导的I型干扰素诱导。因此，我们假设TIR8/SIGIRR是一种内源性TLR抑制剂，可以预防石油诱导的SLE。SIGIRR缺陷的树突状细胞在体外表达更高水平的TLR7，TLR7激活导致IL-12产生增加。在体内，缺乏SIGIRR后6个月，脾CD11c(+)树突状细胞表面CD40的表达增加，MX-1、TNF、IL-12、BAFF和bcl2的mRNA表达增加。Sigirr(-/-)小鼠脾细胞中的CD4(-)/CD8(-)自身反应性T细胞和B220(+)B细胞计数也增加。血清自身抗体分析显示，Sigirr缺乏症特异性地促进类风湿因子(4个月龄)和抗sNRNP-Ig G(5个月龄)的产生，而抗Smith-Ig G或抗dsDNA-Ig G与Sigirr基因无关。这种作用足以显著加重Sigirr缺陷小鼠的狼疮性肾炎。结构模型预测发现SIGIRR胞内TIR结构域的BB环与TLR7和MyD88相互作用。BB环的缺失足以完全消除SIGIRR对TLR7信号的抑制作用。因此，TIR8/SIGIRR通过其细胞内BB环抑制TLR7介导的树突状细胞的激活，从而预防碳氢化合物油诱导的狼疮。版权所有(C)2009年英国和爱尔兰病理学会。作者：John Wiley&Sons，Ltd.
Multiple genetic factors contribute to the clinical variability of spontaneous systemic lupus erythematosus (SLE) but their role in drug-induced SLE remain largely unknown. Hydrocarbon oil-induced SLE depends on mesothelial cell apoptosis and Toll-like receptor (TLR)-7-mediated induction of type I interferons. Hence, we hypothesized that TIR8/SIGIRR, an endogenous TLR inhibitor, prevents oil-induced SLE. Sigirr-deficient dendritic cells expressed higher TLR7 mRNA levels and TLR7 activation resulted in increased IL-12 production in vitro. In vivo, lack of SIGIRR increased surface CD40 expression on spleen CD11c(+) dendritic cells and MX-1, TNF, IL-12, BAFF and BCL-2 mRNA expression 6 months after pristane injection. Spleen cell counts of CD4(-)/CD8(-) 'autoreactive' T cells and B220(+) B cells were also increased in Sigirr(-/-) mice. Serum autoantibody analysis revealed that Sigirr deficiency specifically enhanced the production of rheumatoid factor (from 4 months of age) and anti-snRNP IgG (from 5 months of age), while anti-Smith IgG or anti-dsDNA IgG were independent of the Sigirr genotype. This effect was sufficient to significantly aggravate lupus nephritis in Sigirr-deficient mice. Structure model prediction identified the BB loop of SIGIRR's intracellular TIR domain to interact with TLR7 and MyD88. BB loop deletion was sufficient to completely abrogate SIGIRR's inhibitory effect on TLR7 signalling. Thus, TIR8/SIGIRR protects from hydrocarbon oil-induced lupus by suppressing the TLR7-mediated activation of dendritic cells, via its intracellular BB loop. Copyright (C) 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.