The Toll-interleukin-1 receptor member SIGIRR regulates colonic epithelial homeostasis, inflammation, and tumorigenesis
The Toll-interleukin-1 receptor member SIGIRR regulates colonic epithelial homeostasis, inflammation, and tumorigenesis
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DOI：
10.1016/j.immuni.2007.02.012
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发表时间：
2007-04-01
期刊：
影响因子：
32.4
通讯作者：
Li, Xiaoxia
中科院分区：
文献类型：
--
作者：
Xiao, Hui;Gulen, Muhammet Fatih;Li, Xiaoxia
尽管结肠粘膜与大量肠道细菌持续接触，但通常对这些潜在的促炎信号反应迟钝。在这里，我们报告说，单一的免疫球蛋白IL-1受体相关分子（SIGIRR），Toll-IL-1R信号的负调节，发挥了关键作用，在肠道内稳态，肠道炎症和结肠炎相关的肿瘤发生，通过维持微生物的耐受性结肠上皮。SIGIRR缺陷型（Sigirr（-/-））结肠上皮细胞表现出肠道细菌依赖性稳态缺陷，如炎症基因的组成性上调、对葡聚糖硫酸钠（DSS）激发的炎症反应增加以及氧化偶氮甲烷（AOM）+DSS诱导的结肠炎相关肿瘤发生增加所示。在SIGIRR缺陷背景下，SIGIRR转基因的肠上皮特异性表达降低了SIGIRR缺陷结肠上皮的细胞存活率，消除了Sigirr（-/-）小鼠对DSS诱导的结肠炎的超敏反应，并降低了AOM + DSS诱导的肿瘤发生。综上所述，我们的结果表明，上皮来源的SIGIRR在控制结肠对肠道菌群的稳态和先天免疫反应中至关重要。
Despite constant contact with the large population of commensal bacteria, the colonic mucosa is normally hyporesponsive to these potentially proinflammatory signals. Here we report that the single immunoglobulin IL-1 receptor-related molecule (SIGIRR), a negative regulator for Toll-IL-1R signaling, plays a critical role in gut homeostasis, intestinal inflammation, and colitis-associated tumorigenesis by maintaining the microbial tolerance of the colonic epithelium. SIGIRR-deficient (Sigirr(-/-)) colonic epithelial cells displayed commensal bacteria-dependent homeostatic defects, as shown by constitutive upregulation of inflammatory genes, increased inflammatory responses to dextran sulfate sodium (DSS) challenge, and increased Azoxymethane (AOM)+ DSS-induced colitis-associated tumorigenesis. Gut epithelium-specific expression of the SIGIRR transgene in the SIGIRR-deficient background reduced the cell survival of the SIGIRR-cleficient colon epithelium, abrogated the hypersensitivity of the Sigirr(-/-) mice to DSS-induced colitis, and reduced AOM+DSS-induced tumorigenesis. Taken together, our results indicate that epithelium-derived SIGIRR is critical in controlling the homeostasis and innate immune responses of the colon to enteric microflora.