Macrophage-derived EDA-A2 inhibits intestinal stem cells by targeting miR-494/EDA2R/β-catenin signaling in mice.

Lele Song, Renxu Chang, Xia Sun, Liying Lu, Han Gao, Huiying Lu, Ritian Lin, Xiaorong Xu, Zhanju Liu, Lixing Zhan

Communications biology 2021 Feb 16

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The mucosa microenvironment is critical for intestinal stem cell self-renewal and reconstruction of the epithelial barrier in inflammatory bowel disease (IBD), where the mechanisms underlying cross-talk between intestinal crypts and the microenvironment remain unclear. Here, we firstly identified miR-494-3p as an important protector in colitis. miR-494-3p levels were decreased and negatively correlated with the severity in human IBD samples, as well as in colitis mice. In colitis crypts, a notable cytokine-cytokine receptor, miR-494-3p-targeted EDA2R and the ligand EDA-A2, suppressed colonic stemness and epithelial repair by inhibiting β-catenin/c-Myc. In differentiated IECs, miR-494-3p inhibits macrophage recruitment, M1 activation and EDA-A2 secretion by targeting IKKβ/NF-κB in colitis. A miR-494-3p agomir system notably ameliorated the severity of colonic colitis in vivo. Collectively, our findings uncover a miR-494-3p-mediated cross-talk mechanism by which macrophage-induced intestinal stem cell impairment aggravates intestinal inflammation.

Citation

Lele Song, Renxu Chang, Xia Sun, Liying Lu, Han Gao, Huiying Lu, Ritian Lin, Xiaorong Xu, Zhanju Liu, Lixing Zhan. Macrophage-derived EDA-A2 inhibits intestinal stem cells by targeting miR-494/EDA2R/β-catenin signaling in mice. Communications biology. 2021 Feb 16;4(1):213