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J Clin Invest. 2019 Feb 1;129(2):712-726. doi: 10.1172/JCI122085. Epub 2019 Jan 14.

Neutrophil-induced genomic instability impedes resolution of inflammation and wound healing.

Author information

1
Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
2
Enteric Neuroscience Program, Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, Minnesota, USA.
3
Department of Cell and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
4
Department of Physiology & Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, USA.
5
Department of Obstetrics and Gynecology, Ulm University, Ulm, Germany.
6
Northwestern Memorial Hospital, 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.

KEYWORDS:

DNA repair; Gastroenterology; Inflammation; Inflammatory bowel disease; Neutrophils

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