Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Metidji A

PROVIDER: S-EPMC6104739 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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

Metidji Amina A Omenetti Sara S Crotta Stefania S Li Ying Y Nye Emma E Ross Ellie E Li Vivian V Maradana Muralidhara R MR Schiering Chris C Stockinger Brigitta B

Immunity 20180814 2

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 ...[more]

PMID: 30119997

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Project description:Unlike HIV infection, SIV infection is generally nonpathogenic in natural hosts, such as African green monkeys (AGMs), despite life-long high viral replication. Lack of disease progression was reportedly based on the ability of SIV-infected AGMs to prevent gut dysfunction, avoiding microbial translocation and the associated systemic immune activation and chronic inflammation. Yet, the maintenance of gut integrity has never been documented, and the mechanism(s) by which gut integrity is preserved are unknown. We sought to investigate the early events of SIV infection in AGMs, specifically examining the impact of SIVsab infection on the gut mucosa. Twenty-nine adult male AGMs were intrarectally infected with SIVsab92018 and serially sacrificed at well-defined stages of SIV infection, preramp-up (1-3 days post-infection (dpi)), ramp-up (4-6 dpi), peak viremia (9-12 dpi), and early chronic SIV infection (46-55 dpi), to assess the levels of immune activation, apoptosis, epithelial damage and microbial translocation in the GI tract and peripheral lymph nodes. Tissue viral loads, plasma cytokines and plasma markers of gut dysfunction were also measured throughout the course of early infection. While a strong, but transient, interferon-based inflammatory response was observed, the levels of plasma markers linked to enteropathy did not increase. Accordingly, no significant increases in apoptosis of either mucosal enterocytes or lymphocytes, and no damage to the mucosal epithelium were documented during early SIVsab infection of AGMs. These findings were supported by RNAseq of the gut tissue, which found no significant alterations in gene expression that would indicate microbial translocation. Thus, for the first time, we confirmed that gut epithelial integrity is preserved, with no evidence of microbial translocation, in AGMs throughout early SIVsab infection. This might protect AGMs from developing intestinal dysfunction and the subsequent chronic inflammation that drives both HIV disease progression and HIV-associated comorbidities.

Dataset Information

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

Publications

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

Similar Datasets

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