The Environmental Sensor AHR Protects from Inflammatory Damage by Maintaining Intestinal Stem Cell Homeostasis and Barrier Integrity

被引：343

作者：

Metidji, Amina ^{[1
]}

Omenetti, Sara ^{[1
]}

Crotta, Stefania ^{[1
]}

Li, Ying ^{[1
]}

Nye, Emma ^{[1
]}

Ross, Ellie ^{[2
]}

Li, Vivian ^{[1
]}

Maradana, Muralidhara R. ^{[1
]}

Schiering, Chris ^{[1
,3
]}

Stockinger, Brigitta ^{[1
]}

机构：

[1] Francis Crick Inst, London NW1 1AT, England

[2] Univ London, Royal Vet Coll, London, England

[3] Imperial Coll, Hammersmith Hosp, Med Res Council London Inst Med Sci, London W12 0NN, England

来源：

IMMUNITY | 2018年 / 49卷 / 02期

基金：

英国惠康基金; 英国医学研究理事会;

关键词：

ARYL-HYDROCARBON RECEPTOR; COLORECTAL-CANCER; DIOXIN RECEPTOR; LIGANDS; INDOLE-3-CARBINOL; SUSCEPTIBILITY; ACTIVATION; TRYPTOPHAN; NUTRITION; PATHWAYS;

D O I：

10.1016/j.immuni.2018.07.010

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

071005 [微生物学]; 100108 [医学免疫学];

摘要：

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-beta-catenin signaling and restrict ISC proliferation. Thus, activation of the AHR pathway in IECs guards the stem cell niche to maintain intestinal barrier integrity.

引用

页码：353 / +

页数：15

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