The Environmental Sensor AHR Protects from Inflammatory Damage by Maintaining Intestinal Stem Cell Homeostasis and Barrier Integrity.
The Environmental Sensor AHR Protects from Inflammatory Damage by Maintaining Intestinal Stem Cell Homeostasis and Barrier Integrity.
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DOI：
10.1016/j.immuni.2018.07.010
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发表时间：
2018-08-21
期刊：
影响因子：
32.4
通讯作者：
Stockinger B
中科院分区：
文献类型：
--
作者：
Metidji A;Omenetti S;Crotta S;Li Y;Nye E;Ross E;Li V;Maradana MR;Schiering C;Stockinger B
肠道的上皮组织和免疫小室不断暴露在波动的外部环境中。这一屏障表面的这些隔室之间的通信缺陷是感染和慢性炎症的易感性的基础。环境因素在肠道内稳态中扮演着重要的角色，但机制上知之甚少。我们发现肠上皮细胞(IECS)在受到感染或化学损伤时的再生受到环境感受器芳烃受体(AHR)的深刻影响。IEC特异性的AhR缺失导致肠道干细胞(ISC)不受限制的增殖和分化受阻，导致未能控制弓形虫的感染，最终导致恶变。膳食配体激活AHR可恢复屏障动态平衡，保护干细胞生态位，并通过转录调控RNF43和ZnRF3，E3泛素连接酶抑制Wnt-β-catenin信号转导和限制间质干细胞增殖，从而防止肿瘤发生。因此，IECS中AHR途径的激活保护了干细胞生态位，以维持肠道屏障的完整性。促肾上腺皮质激素释放激素缺乏促进炎症和结肠肿瘤的发生，促肾上腺皮质激素释放激素激活调节肠隐窝干细胞分化，调节WNT-β-连环蛋白途径的负调控。富含促肾上腺皮质激素受体配体的饮食可以预防或阻止肿瘤发生。研究表明，肠道上皮细胞中AhR基因的缺失会导致肠道干细胞(ISCs)屏障的缺陷和不受限制的增殖，最终导致恶变。由饮食配体激活的AHR保护ISC生态位并维持肠道屏障动态平衡。
The epithelium and immune compartment in the intestine are constantly exposed to a fluctuating external environment. Defective communication between these compartments at this barrier surface underlies susceptibility to infections and chronic inflammation. Environmental factors play a significant, but mechanistically poorly understood, role in intestinal homeostasis. We found that regeneration of intestinal epithelial cells (IECs) upon injury through infection or chemical insults was profoundly influenced by the environmental sensor aryl hydrocarbon receptor (AHR). IEC-specific deletion of Ahr resulted in failure to control C. rodentium infection due to unrestricted intestinal stem cell (ISC) proliferation and impaired differentiation, culminating in malignant transformation. AHR activation by dietary ligands restored barrier homeostasis, protected the stem cell niche, and prevented tumorigenesis via transcriptional regulation of of Rnf43 and Znrf3, E3 ubiquitin ligases that inhibit Wnt-β-catenin signaling and restrict ISC proliferation. Thus, activation of the AHR pathway in IECs guards the stem cell niche to maintain intestinal barrier integrity. AHR deficiency in IECs promotes inflammation and colon tumorigenesis AHR activation regulates intestinal crypt stem cell differentiation AHR controls negative regulators of the Wnt-β-catenin pathway A diet rich in AHR ligands can prevent or halt tumorigenesis Metidji et al. show that deletion of Ahr in intestinal epithelial cells results in a defective barrier and unrestricted proliferation of intestinal stem cells (ISCs), culminating in malignant transformation. Activation of AHR by dietary ligands guards the ISC niche and maintains intestinal barrier homeostasis.
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影响因子：
4.6
作者：
Hubbard TD;Murray IA;Bisson WH;Lahoti TS;Gowda K;Amin SG;Patterson AD;Perdew GH
通讯作者：
Perdew GH
影响因子：
5.3
作者：
Luecke-Johansson, Sandra;Gralla, Michael;Poellinger, Lorenz
通讯作者：
Poellinger, Lorenz
影响因子：
64.8
作者：
Hao, Huai-Xiang;Xie, Yang;Cong, Feng
通讯作者：
Cong, Feng
DOI：
10.1073/pnas.88.21.9543
发表时间：
1991-11-01
影响因子：
11.1
作者：
BJELDANES, LF;KIM, JY;BRADFIELD, CA
通讯作者：
BRADFIELD, CA
影响因子：
64.8
作者：
Koo, Bon-Kyoung;Spit, Maureen;Clevers, Hans
通讯作者：
Clevers, Hans