miR147 promotes mucosal integrity and healing in intestinal inflammation

TL;DR

miR147 helps protect the intestinal lining and reduce inflammation, and its absence worsens gut inflammation, making it a potential treatment target for inflammatory bowel disease.

Contribution

miR147 is newly identified as a regulator of intestinal mucosal healing and inflammation through its regulation of Ndufa4.

Findings

miR147-deficient mice showed increased intestinal inflammation and reduced mucosal healing during colitis.

Ndufa4 is a likely miR147 target, with elevated levels in miR147-deficient mice correlating with inflammation.

Spatial transcriptomic analyses confirmed a regulatory relationship between miR147 and Ndufa4 in epithelial cells.

Abstract

The intestinal mucosal epithelium forms a barrier between luminal contents and the body. MicroRNAs (miRNAs) regulate mucosal homeostasis by controlling inflammatory responses and structural integrity. Here, we discovered a protective role for miR147 in intestinal inflammation using a miR147tdTomato reporter mouse. miR147 was enriched in the intestines, with the highest expression in the colonic epithelial cells at the luminal surface, with prominent expression in differentiated enterocytes. Mice with general or intestinal epithelial deletion of miR147 showed increased intestinal inflammation and diminished mucosal healing during colitis. RNA sequencing of miR147-deficient cells showed dysregulated immune signaling, with upregulated proinflammatory cytokine pathways and reduced type I interferon responses and revealed Ndufa4 as a likely miR147 target. Ndufa4, a mitochondrial protein regulating energy metabolism and inflammation, was elevated at the crypt base, inversely correlating with miR147. Mice lacking the miR147 binding site in Ndufa4’s 3′-UTR phenocopied miR147-deficient mice during colitis. Spatial and single-cell transcriptomic analyses in murine and human colons showed mutually exclusive miR147 and Ndufa4 expression, consistent with a regulatory relationship in epithelial differentiation and metabolism. These findings underscore miR147’s role in intestinal homeostasis and mucosal healing, suggesting it as a therapeutic target for inflammatory bowel disease.

miR-147 protects against intestinal inflammation by regulating immune responses and mucosal healing. Its absence impairs healing, suggesting miR-147 as a potential target for inflammatory bowel disease treatment.

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