The AIM2 inflammasome is a central regulator of intestinal homeostasis through the IL-18/IL-22/STAT3 pathway.
The AIM2 inflammasome is a central regulator of intestinal homeostasis through the IL-18/IL-22/STAT3 pathway.
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DOI：
10.1038/cmi.2016.35
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发表时间：
2017-01
影响因子：
24.1
通讯作者：
中科院分区：
文献类型：
--
作者：
炎症体对维持肠道内环境稳定非常重要，而生物失调是炎症性肠病(IBD)的病理基础，并增加了患结直肠癌的风险。炎性小体缺陷会导致小鼠的慢性肠道炎症，并增加对结肠炎的易感性。然而，黑色素瘤缺失的炎症体感受器2(AIM2)通过DNA依赖的蛋白激酶和Akt通路以非炎症体依赖的方式保护结直肠癌。然而，AIM2炎症体在IBD和结直肠癌早期的作用仍不明确。在这里，我们证明了AIM2炎症体在肠道中具有保护作用。在稳定状态下，AIM2缺失导致IL-18分泌丧失，肠上皮细胞IL-22结合蛋白(IL-22BP)受到抑制，从而导致STAT3依赖的抗菌肽(AMP)Reg3β和Reg3γ丢失，从而促进失调相关性结肠炎。在葡聚糖硫酸钠诱导的结肠炎过程中，AIM2−/−小鼠体内功能失调的IL-18/IL-22BP通路促进了IL-22的过度产生和STAT3的激活。AIM2−/−小鼠在Reg3b和Reg3g表达增强的结肠炎缓解过程中进一步表现出持续的STAT3和Akt激活。这种自我维持的机制促进了肠道隐窝细胞的增殖，并可能是最近描述的AIM2−/−小鼠对结直肠癌易感性增加的原因之一。总之，我们的结果表明，AIM2炎症体通过调节IL-18/IL-22BP/IL-22和STAT3途径以及部分AMP的表达，在预防生物失调和肠道炎症中发挥核心作用。
Inflammasomes are important for maintaining intestinal homeostasis, and dysbiosis contributes to the pathology of inflammatory bowel disease (IBD) and increases the risk for colorectal cancer. Inflammasome defects contribute to chronic intestinal inflammation and increase the susceptibility to colitis in mice. However, the inflammasome sensor absent in melanoma 2 (AIM2) protects against colorectal cancer in an inflammasome-independent manner through DNA-dependent protein kinase and Akt pathways. Yet, the roles of the AIM2 inflammasome in IBD and the early phases of colorectal cancer remain ill-defined. Here we show that the AIM2 inflammasome has a protective role in the intestine. During steady state, Aim2 deletion results in the loss of IL-18 secretion, suppression of the IL-22 binding protein (IL-22BP) in intestinal epithelial cells and consequent loss of the STAT3-dependent antimicrobial peptides (AMPs) Reg3β and Reg3γ, which promotes dysbiosis-linked colitis. During dextran sulfate sodium-induced colitis, a dysfunctional IL-18/IL-22BP pathway in Aim2−/− mice promotes excessive IL-22 production and elevated STAT3 activation. Aim2−/− mice further exhibit sustained STAT3 and Akt activation during the resolution of colitis fueled by enhanced Reg3b and Reg3g expression. This self-perpetuating mechanism promotes proliferation of intestinal crypt cells and likely contributes to the recently described increase in susceptibility of Aim2−/− mice to colorectal cancer. Collectively, our results demonstrate a central role for the AIM2 inflammasome in preventing dysbiosis and intestinal inflammation through regulation of the IL-18/IL-22BP/IL-22 and STAT3 pathway and expression of select AMPs.
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影响因子：
32.4
作者：
de Almeida L;Khare S;Misharin AV;Patel R;Ratsimandresy RA;Wallin MC;Perlman H;Greaves DR;Hoffman HM;Dorfleutner A;Stehlik C
通讯作者：
Stehlik C
影响因子：
64.8
作者：
Buczacki, Simon J. A.;Zecchini, Heather Ireland;Winton, Douglas J.
通讯作者：
Winton, Douglas J.
DOI：
10.1186/2045-9769-2-2
发表时间：
2013
期刊：
Cell regeneration (London, England)
影响因子：
--
作者：
Hill T;Krougly O;Nikoopour E;Bellemore S;Lee-Chan E;Fouser LA;Hill DJ;Singh B
通讯作者：
Singh B
影响因子：
24.5
作者：
Bauer, Christian;Duewell, Peter;Schnurr, Max
通讯作者：
Schnurr, Max
影响因子：
4.9
作者：
Carey, Rebecca;Jurickova, Ingrid;Denson, Lee A.
通讯作者：
Denson, Lee A.