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Neutrophil‐induced genomic instability impedes resolution of inflammation and wound healing
Author(s) -
Sumagin Ronen,
Bui Triet M,
Wiesolek Hannah L,
ButinIsraeli Veronika
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.34.10
Subject(s) - wound healing , inflammation , rad51 , genome instability , cancer research , immunology , biology , homologous recombination , medicine , dna damage , gene , dna , genetics
Neutrophil (PMN) infiltration of the intestinal mucosa is a hallmark of tissue injury associated with inflammatory bowel diseases (IBD). The pathological effects of PMNs are largely attributed to the release of soluble mediators and reactive oxygen species (ROS). We identified a new, ROS‐independent mechanism, whereby activated, tissue‐infiltrating PMNs release microparticles armed with pro‐inflammatory microRNAs (miR‐23a and miR‐155). Using IBD clinical samples, in vitro and in vivo injury models, we show that PMN‐derived miR‐23a/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/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, wound healing and potentially prevent neoplasia. Support or Funding Information This work was supported by grants from the National Institutes of Health (NIH) DK101675, Digestive Health Foundation, Chicago and by the Robert H. Lurie Comprehensive Cancer Center(Eisenberg Scholar grant). This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .