MicroRNA-21 Knockout Improve the Survival Rate in DSS Induced Fatal Colitis through Protecting against Inflammation and Tissue Injury

Abstract

BackgroundMicroRNA-21 (miR-21) is overexpressed in most inflammatory diseases, but its physiological role in gut inflammation and tissue injury is poorly understood. The goal of this work is to understand the role of miR-21 in colitis and damage progression of intestine in a genetically modified murine model.MethodsExperimental colitis was induced in miR-21 KO and wild-type (WT) mice by 3.5% dextran sulphate sodium (DSS) administration for 7 days. Disease activity index(DAI), blood parameters, intestinal permeability, histopathologic injury, cytokine and chemokine production, and epithelial cells apoptosis were examined in colons of miR-21 KO and WT mice.ResultsmiR-21 was overexpressed in intestine of inflammatory bowel diseases (IBD) and acute intestinal obstruction (AIO) patients when compared with normal intestinal tissues. Likewise, miR-21 was up-regulated in colon of IL-10 KO mice when compared with control mice. WT mice rapidly lost weight and were moribund 5 days after treatment with 3.5% DSS, while miR-21 KO mice survived for at least 6 days. Elevated leukocytes and more severe histopathology were observed in WT mice when compared with miR-21 KO mice. Elevated levels of TNF-α and macrophage inflammatory protein-2(MIP-2) in colon culture supernatants from WT mice exhibited significant higher than miR-21 KO mice. Furthermore, CD3 and CD68 positive cells, intestinal permeability and apoptosis of epithelial cells were significantly increased in WT mice when compared with miR-21 KO mice. Finally, we found that miR-21 regulated the intestinal barrier function through modulating the expression of RhoB and CDC42.ConclusionOur results suggest that miR-21 is overexpressed in intestinal inflammation and tissue injury, while knockout of miR-21 in mice improve the survival rate in DSS-induced fatal colitis through protecting against inflammation and tissue injury. Therefore, attenuated expression of miR-21 in gut may prevent the onset or progression of inflammatory bowel disease in patients.

Matrix metalloproteinase 9-induced increase in intestinal epithelial tight junction permeability contributes to the severity of experimental DSS colitis

“…In agreement with others and our previous reports (38,46,61), the DSS administration significantly increased colonic dextran flux in WT mice. The DSS-induced increase in colonic permeability was associated with a marked increase in MMP-9 expression in intestinal epithelial cells in WT mice; the DSS-induced increase in colonic permeability was significantly attenuated in MMP-9 Ϫ/Ϫ mice.…”

Implication of miRNAs for inflammatory bowel disease treatment: Systematic review

“…They demonstrated that overexpression of miR-21 in patients with UC and Caco-2 cells impaired intestinal tight junction integrity and morphology through targeting RhoB. Similarly, Shi et al [53] reported that miR-21 was overexpressed in IBD patients, IL-10 KO mice and DSS-treated mice. MiR-21 knockout (KO) mice was less susceptible to experimental colitis and had more ameliorative inflammatory responses than wild type (WT) mice.…”

MicroRNA-21 promotes Th17 differentiation and mediates experimental autoimmune encephalomyelitis

“…Specifically, our study corroborates the previous observation that miR-21 is overexpressed in the CNS-infiltrating T cells of animals with EAE (67) and is consistent with miR-21 involvement in other autoimmune disease models. For example, silencing miR-21 in vivo has led to a significant reduction of splenomegaly in lupus mice (68), targeted ablation of miR-21 has led to reduced lung eosinophilia after allergen challenge in mice (69), and most recently, Mir21 -/-mice have been shown to be resistant to dextran sulfate sodium-induced (DSS-induced) colitis (70). Supporting these animal models, increased expression inhibitor developed EAE.…”