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Updated: Jan 30, 2026
Murine Endoscopy for In Vivo Multimodal Imaging of Carcinogenesis and Assessment of Intestinal Wound Healing and Inflammation
Published on: August 26, 2014
Neutrophil-induced genomic instability impedes resolution of inflammation and wound healing
Veronika Butin-Israeli1, Triet M Bui1, Hannah L Wiesolek1
1Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Abstract:
Neutrophil (PMN) infiltration of the intestinal mucosa is a hallmark of tissue injury associated with inflammatory bowel diseases (IBDs). The pathological effects of PMNs are largely attributed to the release of soluble mediators and reactive oxygen species (ROS). We identified what we believe is a new, ROS-independent mechanism whereby activated tissue-infiltrating PMNs release microparticles armed with proinflammatory microRNAs (miR-23a and miR-155). Using IBD clinical samples, and in vitro and in vivo injury models, we show that PMN-derived miR-23a and miR-155 promote accumulation of double-strand breaks (DSBs) by inducing lamin B1-dependent replication fork collapse and inhibition of homologous recombination (HR) by targeting HR-regulator RAD51. DSB accumulation in injured epithelium led to impaired colonic healing and genomic instability. Targeted inhibition of miR-23a and miR-155 in cultured intestinal epithelial cells and in acutely injured mucosa decreased the detrimental effects of PMNs and enhanced tissue healing responses, suggesting that this approach can be used in therapies aimed at resolution of inflammation, in wound healing, and potentially to prevent neoplasia.
Insights
Inflammatory bowel disease involves neutrophils releasing microRNAs (miR-23a, miR-155) that damage DNA, impairing gut healing. Inhibiting these microRNAs promotes tissue repair and may prevent cancer.
Area of Science:
- Gastroenterology
- Molecular Biology
- Immunology
Background:
- Neutrophil infiltration is key in inflammatory bowel disease (IBD) tissue injury.
- Pathological effects of neutrophils are linked to soluble mediators and reactive oxygen species (ROS).
Purpose of the Study:
- To identify a novel ROS-independent mechanism of neutrophil-mediated intestinal injury.
- To investigate the role of specific microRNAs in IBD pathogenesis and tissue repair.
Main Methods:
- Analysis of IBD clinical samples.
- In vitro and in vivo intestinal injury models.
- Assessment of microRNA (miR-23a, miR-155) effects on DNA double-strand breaks (DSBs) and homologous recombination (HR).
- Targeted inhibition of miR-23a and miR-155.
Main Results:
- Activated neutrophils release microparticles containing miR-23a and miR-155.
- These microRNAs induce DSBs by replication fork collapse and inhibit HR by targeting RAD51.
- DSB accumulation impairs colonic healing and causes genomic instability.
- Inhibition of miR-23a and miR-155 enhances tissue healing.
Conclusions:
- Neutrophil-derived miR-23a and miR-155 represent a novel mechanism of IBD-associated tissue injury.
- Targeting these microRNAs offers a potential therapeutic strategy for IBD, wound healing, and neoplasia prevention.
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