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

Veronika Butin-Israeli; Triet M. Bui; Hannah L. Wiesolek; Lorraine Mascarenhas; Joseph J. Lee; Lindsey C. Mehl; Kaitlyn R. Knutson; Stephen A. Adam; Robert D. Goldman; Arthur Beyder; Lisa Wiesmuller; Stephen B. Hanauer; Ronen Sumagin

doi:10.1172/JCI122085

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

Veronika Butin-Israeli^*, Triet M. Bui, Hannah L. Wiesolek, Lorraine Mascarenhas, Joseph J. Lee, Lindsey C. Mehl, Kaitlyn R. Knutson, Stephen A. Adam, Robert D. Goldman, Arthur Beyder, Lisa Wiesmuller, Stephen B. Hanauer, Ronen Sumagin

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

136 Scopus citations

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.

Original language	English (US)
Pages (from-to)	712-726
Number of pages	15
Journal	Journal of Clinical Investigation
Volume	129
Issue number	2
DOIs	https://doi.org/10.1172/JCI122085
State	Published - Feb 1 2019

Funding

This work was supported by grants from the National Institutes of Health (DK101675), Digestive Health Foundation, Chicago, a Research Scholar Grant by the American Cancer Society (RSG-17-235-01-CSM), and by the Robert H. Lurie Comprehensive Cancer Center (Eisenberg Scholar grant). We thank the Northwestern University Center for Advanced Microscopy core (supported by a National Cancer Institute Cancer Center Support Grant P30 CA060553, awarded to the Robert H. Lurie Comprehensive Cancer Center) for help with the imaging experiments. The colonoids/ organoid work was supported by the Mayo Clinic Center for Cell Signaling in Gastroenterology (National Institute of Diabetes and Digestive and Kidney Diseases, P30DK084567) and Lisa Boardman (clinical core).

ASJC Scopus subject areas

General Medicine

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Butin-Israeli, V., Bui, T. M., Wiesolek, H. L., Mascarenhas, L., Lee, J. J., Mehl, L. C., Knutson, K. R., Adam, S. A., Goldman, R. D., Beyder, A., Wiesmuller, L., Hanauer, S. B., & Sumagin, R. (2019). Neutrophil-induced genomic instability impedes resolution of inflammation and wound healing. Journal of Clinical Investigation, 129(2), 712-726. https://doi.org/10.1172/JCI122085

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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.",

author = "Veronika Butin-Israeli and Bui, {Triet M.} and Wiesolek, {Hannah L.} and Lorraine Mascarenhas and Lee, {Joseph J.} and Mehl, {Lindsey C.} and Knutson, {Kaitlyn R.} and Adam, {Stephen A.} and Goldman, {Robert D.} and Arthur Beyder and Lisa Wiesmuller and Hanauer, {Stephen B.} and Ronen Sumagin",

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

Abstract

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