The DNA Sensor AIM2 Maintains Intestinal Homeostasis via Regulation of Epithelial Antimicrobial Host Defense.
The DNA Sensor AIM2 Maintains Intestinal Homeostasis via Regulation of Epithelial Antimicrobial Host Defense.
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DOI：
10.1016/j.celrep.2015.10.040
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发表时间：
2015-12-01
期刊：
影响因子：
8.8
通讯作者：
Zaki MH
中科院分区：
文献类型：
--
作者：
Hu S;Peng L;Kwak YT;Tekippe EM;Pasare C;Malter JS;Hooper LV;Zaki MH
肠道中的微生物模式分子通过不同的模式识别受体发挥免疫调节作用。然而，细胞溶质DNA传感器AIM 2在维持肠道稳态中的作用尚不清楚。在这里，我们表明Aim 2 −/−小鼠对葡聚糖硫酸钠诱导的结肠炎高度敏感，这与微生物生态失调有关，如大肠杆菌的结肠负荷较高。无菌小鼠与Aim 2 −/−小鼠微生物群的定殖导致更高的结肠炎易感性。对AIM 2介导的宿主防御反应的深入研究表明，在Aim 2 −/−小鼠结肠中，caspase-1活化以及IL-1β和IL-18的产生受到损害，这与炎性小体功能缺陷一致。此外，IL-18输注降低E.大肠杆菌负荷以及结肠炎易感性在Aim 2 −/−小鼠。炎性小体缺陷小鼠中改变的微生物群与肠上皮细胞中几种抗菌肽的表达减少相关。总之，这些发现暗示AIM 2的DNA传感是维持肠道稳态的调节机制。
Microbial pattern molecules in the intestine play immunoregulatory roles via diverse pattern recognition receptors. However, the role of the cytosolic DNA sensor AIM2 in the maintenance of intestinal homeostasis is unknown. Here, we show that Aim2−/− mice are highly susceptible to dextran sodium sulfate-induced colitis which is associated with microbial dysbiosis as represented by higher colonic burden of commensal Escherichia coli. Colonization of germ-free mice with Aim2−/− mouse microbiota leads to higher colitis susceptibility. In-depth investigation of AIM2-mediated host defense responses reveals that caspase-1 activation and IL-1β and IL-18 production are compromised in Aim2−/− mouse colons, consistent with defective inflammasome function. Moreover, IL-18 infusion reduces E. coli burden as well as colitis susceptibility in Aim2−/− mice. Altered microbiota in inflammasome-defective mice correlate with reduced expression of several antimicrobial peptides in intestinal epithelial cells. Together, these findings implicate DNA sensing by AIM2 as a regulatory mechanism for maintaining intestinal homeostasis.