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NCoR1 Protects Mice From Dextran Sodium Sulfate-Induced Colitis by Guarding Colonic Crypt Cells From Luminal Insult.

ABSTRACT: BACKGROUND & AIMS:Colonic stem cells are essential for producing the mucosal lining, which in turn protects stem cells from insult by luminal factors. Discovery of genetic and biochemical events that control stem cell proliferation and differentiation can be leveraged to decipher the causal factors of ulcerative colitis and aid the development of more effective therapy. METHODS:We performed in vivo and in vitro studies from control (nuclear receptor corepressor 1 [NCoR1F/F]) and intestinal epithelial cell-specific NCoR1-deficient mice (NCoR1?IEC). Mice were challenged with dextran sodium sulfate to induce experimental ulcerative colitis, followed by colitis examination, barrier permeability analysis, cell proliferation immunostaining assays, and RNA sequencing analysis. By using crypt cultures, the organoid-forming efficiency, cell proliferation, apoptosis, and histone acetylation were analyzed after butyrate and/or tumor necrosis factor ? treatments. RESULTS:NCoR1?IEC mice showed a dramatic increase in disease severity in this colitis model, with suppression of proliferative cells at the crypt base as an early event and a concomitant increase in barrier permeability. Genome expression patterns showed an important role for NCoR1 in colonic stem cell proliferation and secretory cell differentiation. Colonic organoids cultured from NCoR1?IEC mice were more sensitive to butyrate-induced cell growth inhibition and apoptosis, which were exaggerated further by tumor necrosis factor ? co-treatment, which was accompanied by increased histone acetylation. CONCLUSIONS:NCoR1 regulates colonic stem cell proliferation and secretory cell differentiation. When NCoR1 is disrupted, barrier protection is weakened, allowing luminal products such as butyrate to penetrate and synergistically damage the colonic crypt cells. Transcript profiling: RNA sequencing data have been deposited in the GEO database, accession number: GSE136153.

SUBMITTER: Mennillo E

PROVIDER: S-EPMC7229481 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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NCoR1 Protects Mice From Dextran Sodium Sulfate-Induced Colitis by Guarding Colonic Crypt Cells From Luminal Insult.

Mennillo Elvira E Yang Xiaojing X Paszek Miles M Auwerx Johan J Benner Christopher C Chen Shujuan S

Cellular and molecular gastroenterology and hepatology 20200207 1

<h4>Background & aims</h4>Colonic stem cells are essential for producing the mucosal lining, which in turn protects stem cells from insult by luminal factors. Discovery of genetic and biochemical events that control stem cell proliferation and differentiation can be leveraged to decipher the causal factors of ulcerative colitis and aid the development of more effective therapy.<h4>Methods</h4>We performed in vivo and in vitro studies from control (nuclear receptor corepressor 1 [NCoR1<sup>F/F</s ...[more]

PMID: 32044398

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Project description:The microenvironment of injured mucosa has important effects on intestinal stem cell self-renewal and reconstruction of epithelial barrier function in inflammatory bowel disease (IBD). However, the precise status of the interactions between intestinal epithelial cell (IEC) injury, particularly intestinal crypt absence, and microenvironment in IBD is not completely understood. We identified miR-494-3p as important for protection of colonic stemness in intestinal inflammation colonic organoid culture. A novel cytokine-cytokine receptor, EDA-A2/EDA2R, could suppress colonic stemness and epithelial repair during IBD. During intestinal inflammation, high level of LP macrophage-derived EDA-A2 inhibited the nuclear β-catenin/c-Myc axis and organoid growth by targeting EDA2R in colonic crypt stem cells. We further demonstrated that the pro-inflammatory cytokines IL-1β and IL-6 are capable of stimulating macrophages to release EDA-A2 during colitis. Secondly, we identified the cross-talk among IECs, colonic crypts, and lamina propria (LP) macrophages in miR-494-3p-mediated colitis. Furthermore, our study showed that miR-494-3p deficiency in IECs promoted LP macrophage recruitment and M1 activation in DSS-induced colitis mice. In addition, we identified miR-494-3p as critical to dampening IEC injury; specifically, miR-494-3p inhibited inflammation-induced IKKβ/NF-κB activation by targeting the IKKβ 3’UTR in IECs. As such, administration of adequate amounts of a miR-494-3p agomire attenuate colitis in vivo. Consistent with this inference, we showed that miR-494-3p levels were decreased in colonic crypts and serum in colitis mice, and loss of miR-494 potentiated the severity of colonic colitis. Our clinical data on the interactions between miR-494-3p levels in serum exosomes & colonic tissues and associated outcomes support the clinical relevance of miR-494-3p in IBD. The miR-494-3p agomir system, which we designed permits local delivery in vivo in this study, significantly ameliorated the severity of colonic colitis. Our findings no only uncover a miR-494-3p-mediated cross-talk mechanism by which inflamed colonic LP macrophages integrate signals from IECs to regulate colonic stemness and colonic epithelial repair/homeostasis. The miR-494-3p agomir may serve as a potential therapeutic approach in IBD.

Dataset Information

NCoR1 Protects Mice From Dextran Sodium Sulfate-Induced Colitis by Guarding Colonic Crypt Cells From Luminal Insult.

Publications

NCoR1 Protects Mice From Dextran Sodium Sulfate-Induced Colitis by Guarding Colonic Crypt Cells From Luminal Insult.

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