MicroRNA-21 knockout improve the survival rate in DSS induced fatal colitis through protecting against inflammation and tissue injury

PLoS One. 2013 Jun 24;8(6):e66814. doi: 10.1371/journal.pone.0066814. Print 2013.

Abstract

Background: MicroRNA-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.

Methods: Experimental 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.

Results: miR-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.

Conclusion: Our 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Colitis / blood
  • Colitis / genetics*
  • Colitis / pathology*
  • Cytokines / biosynthesis
  • Dextran Sulfate
  • Disease Susceptibility
  • Epithelial Cells / pathology
  • Gene Expression Regulation
  • Inflammation / genetics*
  • Inflammation / pathology*
  • Intestinal Mucosa / metabolism*
  • Intestinal Mucosa / pathology
  • Intestines / pathology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Permeability
  • Survival Analysis

Substances

  • Cytokines
  • MIRN21 microRNA, mouse
  • MicroRNAs
  • Dextran Sulfate

Grant support

This work was supported by grants from National Natural Science Foundation Key projects of China (No.81230057), National Natural Science Foundation of China (No. 81172325), and the Major Basic Research Program of Shanghai (No 12DZ1930502). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.