Essential contribution of IRF3 to intestinal homeostasis and microbiota-mediated Tslp gene induction
Essential contribution of IRF3 to intestinal homeostasis and microbiota-mediated Tslp gene induction
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DOI：
10.1073/pnas.1219482110
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发表时间：
2012-12-18
影响因子：
11.1
通讯作者：
Taniguchi, Tadatsugu
中科院分区：
文献类型：
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作者：
Negishi, Hideo;Miki, Shoji;Taniguchi, Tadatsugu
大肠上皮细胞和免疫细胞暴露于来源于肠道微生物群的多种分子，这些分子可以激活先天性受体，例如Toll样受体（TLR）和视黄酸诱导基因-I样受体（TLR）。尽管已知这些受体的激活对于大肠的稳态是关键的，但是对潜在的基因调控机制还没有很好的理解。在这里，我们表明，干扰素调节因子（IRF）3是至关重要的葡聚糖硫酸钠诱导的结肠炎的抑制。IRF 3缺陷小鼠在结肠炎的炎症和恢复阶段表现出致命的缺陷，伴随着胸腺基质淋巴细胞生成素（TSLP）基因诱导的明显缺陷，TSLP是一种已知对保护大肠至关重要的细胞因子。我们进一步提供证据表明，大肠内容物的DNA和RNA是通过细胞溶质核酸受体激活IRF 3的Tslp基因诱导的关键。我们还证明，IRF 3确实激活Tslp的基因启动子通过IRF-binding序列。这种新鉴定的肠道基因调控机制，其中由微生物源性核酸激活的IRF 3在肠道内稳态中起关键作用，可能在结肠炎性疾病中具有临床意义。
The large intestinal epithelial cells and immune cells are exposed to a variety of molecules derived from commensal microbiota that can activate innate receptors, such as Toll-like receptors (TLRs) and retinoic acid-inducible gene-I-like receptors (RLRs). Although the activation of these receptors is known to be critical for homeostasis of the large intestine, the underlying gene regulatory mechanisms are not well understood. Here, we show that IFN regulatory factor (IRF)3 is critical for the suppression of dextran sulfate sodium-induced colitis. IRF3-deficient mice exhibited lethal defects in the inflammatory and recovery phases of the colitis, accompanied by marked defects in the gene induction for thymic stromal lymphopoietin (TSLP), a cytokine known to be essential for protection of the large intestine. We further provide evidence that DNA and RNA of the large intestinal contents are critical for Tslp gene induction via IRF3 activation by cytosolic nucleic acid receptors. We also demonstrate that IRF3 indeed activates the gene promoter of Tslp via IRF-binding sequences. This newly identified intestinal gene regulatory mechanism, wherein IRF3 activated by microbiota-derived nucleic acids plays a critical role in intestinal homeostasis, may have clinical implication in colonic inflammatory disorders.