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Notch and TNF-? signaling promote cytoplasmic accumulation of OLFM4 in intestinal epithelium cells and exhibit a cell protective role in the inflamed mucosa of IBD patients.

ABSTRACT: Notch signaling is activated in the intestinal epithelial cells (IECs) of patients with inflammatory bowel disease (IBD), and contributes to mucosal regeneration. Our previous study indicated that TNF-? and Notch signaling may synergistically promote the expression of the intestinal stem cell (ISC) marker OLFM4 in human IECs. In the present study, we investigated the gene regulation and function of OLFM4 in human IEC lines. We confirmed that TNF-? and Notch synergistically upregulate the mRNA expression of OLFM4. Luciferase reporter assay showed that OLFM4 transcription is regulated by the synergy of TNF-? and Notch. At the protein level, synergy between TNF-? and Notch promoted cytoplasmic accumulation of OLFM4, which has potential anti-apoptotic properties in human IECs. Analysis of patient-derived tissues and organoids consistently showed cytoplasmic accumulation of OLFM4 in response to NF-?B and Notch activation. Cytoplasmic accumulation of OLFM4 in human IECs is tightly regulated by Notch and TNF-? in synergy. Such cytoplasmic accumulation of OLFM4 may have a cell-protective role in the inflamed mucosa of patients with IBD.

SUBMITTER: Kuno R

PROVIDER: S-EPMC7808948 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Notch and TNF-α signaling promote cytoplasmic accumulation of OLFM4 in intestinal epithelium cells and exhibit a cell protective role in the inflamed mucosa of IBD patients.

Kuno Reiko R Ito Go G Kawamoto Ami A Hiraguri Yui Y Sugihara Hady Yuki HY Takeoka Sayaka S Nagata Sayaka S Takahashi Junichi J Tsuchiya Mao M Anzai Sho S Mizutani Tomohiro T Shimizu Hiromichi H Yui Shiro S Oshima Shigeru S Tsuchiya Kiichiro K Watanabe Mamoru M Okamoto Ryuichi R

Biochemistry and biophysics reports 20210111

Notch signaling is activated in the intestinal epithelial cells (IECs) of patients with inflammatory bowel disease (IBD), and contributes to mucosal regeneration. Our previous study indicated that TNF-α and Notch signaling may synergistically promote the expression of the intestinal stem cell (ISC) marker OLFM4 in human IECs. In the present study, we investigated the gene regulation and function of OLFM4 in human IEC lines. We confirmed that TNF-α and Notch synergistically upregulate the mRNA ex ...[more]

PMID: 33490652

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Project description:BACKGROUND:Myeloid cells, especially mononuclear phagocytes, which include monocytes, macrophages and dendritic cells (DC), play vital roles in innate immunity, and in the initiation and maintenance of adaptive immunity. While T cell-associated activation pathways and cytokines have been identified and evaluated in inflammatory bowel disease (IBD) patients (Neurath, Nat Rev Gastroenterol Hepatol 14:269-78, 1989), the role of mononuclear phagocytes are less understood. Recent reports support the crucial role of DC subsets in the development of acute colitis models (Arimura et al., Mucosal Immunol 10:957-70, 2017), and suggest they may contribute to the pathogenesis of ulcerative colitis (UC) by inducing Th1/Th2/Th17 responses (Matsuno et al., Inflamm Bowel Dis 23:1524-34, 2017). RESULTS:We performed in silico analysis and evaluated the enrichment of immune cells, with a focus on mononuclear phagocytes in IBD patient colonic biopsies. Samples were from different gut locations, with different levels of disease severity, and with treatment response to current therapies. We observe enrichment of monocytes, M1 macrophages, activated DCs (aDCs) and plasmacytoid dendritic cells (pDCs) in inflamed tissues from various gut locations. This enrichment correlates with disease severity. Additionally, the same mononuclear phagocytes subsets are among the top enriched cell types in both infliximab and vedolizumab treatment non-responder samples. We further investigated the enrichment of selected DC and monocyte subsets based on gene signatures derived from a DC- and monocyte-focused single cell RNA-seq (scRNA-seq) study (Villani et al., Science 356:eaah4573, 2017), and verified enrichment in both inflamed tissues and those with treatment resistance. Moreover, we validated an increased mononuclear phagocyte subset abundance in a Dextran Sulphate Sodium (DSS) induced colitis model in C57Bl/6 mice representative of chronic inflammation. CONCLUSIONS:We conducted an extensive analysis of immune cell populations in IBD patient colonic samples and identified enriched subsets of monocytes, macrophages and dendritic cells in inflamed tissues. Understanding how they interact with other immune cells and other cells in the colonic microenvironment such as epithelial and stromal cells will help us to delineate disease pathogenesis.

Dataset Information

Notch and TNF-? signaling promote cytoplasmic accumulation of OLFM4 in intestinal epithelium cells and exhibit a cell protective role in the inflamed mucosa of IBD patients.

Publications

Notch and TNF-α signaling promote cytoplasmic accumulation of OLFM4 in intestinal epithelium cells and exhibit a cell protective role in the inflamed mucosa of IBD patients.

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