The miR-7/EGFR axis controls the epithelial cell immunomodulation and regeneration and orchestrates the pathology in inflammatory bowel disease

Abstract

IntroductionThe epithelial immunomodulation and regeneration are intrinsic critical events against inflammatory bowel disease (IBD). MiR-7 is well documented as a promising regulator in the development of various diseases including inflammatory diseases. ObjectivesThis study aimed to assess the effect of miR-7 in intestinal epithelial cells (IECs) in IBD. MethodsMiR-7def mice were given dextran sulfate sodium (DSS) to induce enteritis model. The infiltration of inflammatory cells was measured by FCM and immunofluorescence assay. 5′deletion assay and EMSA assays were performed to study the regulatory mechanism of miR-7 expression in IECs. The inflammatory signals and the targets of miR-7 were analyzed by RNA-seq and FISH assay. IECs were isolated from miR-7def, miR-7oe and WT mice to identify the immunomodulation and regeneration capacity. IEC-specific miR-7 silencing expression vector was designed and administered by the tail vein into murine DSS-induced enteritis model to evaluate the pathological lesions of IBD. ResultsWe found miR-7 deficiency improved the pathological lesions of DSS-induced murine enteritis model, accompanied by elevated proliferation and enhanced transduction of NF-κB/AKT/ERK signals in colonic IECs, as well as decreased local infiltration of inflammatory cells. MiR-7 was dominantly upregulated in colonic IECs in colitis. Moreover, the transcription of pre-miR-7a-1, orchestrated by transcription factor C/EBPα, was a main resource of mature miR-7 in IECs. As for the mechanism, EGFR, a miR-7 target gene, was downregulated in colonic IECs in colitis model and Crohn's disease patients. Furthermore, miR-7 also controlled the proliferation and inflammatory-cytokine secretion of IECs in response to inflammatory-signals through EGFR/NF-κB/AKT/ERK pathway. Finally, IEC-specific miR-7 silencing promoted the proliferation and transduction of NF-κB pathway in IECs and alleviated the pathological damage of colitis. ConclusionOur results present the unknown role of miR-7/EGFR axis in IEC immunomodulation and regeneration in IBD and might provide clues for the application of miRNA-based therapeutic strategies in colonic diseases.