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

Research output: Contribution to journalArticle

10 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)712-726
Number of pages15
JournalJournal of Clinical Investigation
Volume129
Issue number2
DOIs
StatePublished - Feb 1 2019

Fingerprint

Genomic Instability
Wound Healing
Neutrophils
Homologous Recombination
Inflammation
Inflammatory Bowel Diseases
Reactive Oxygen Species
Lamins
Neutrophil Infiltration
Wounds and Injuries
Intestinal Mucosa
MicroRNAs
Mucous Membrane
Epithelium
Epithelial Cells
Neoplasms
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Butin-Israeli, V., Bui, T. M., Wiesolek, H. L., Mascarenhas, L., Lee, J. J., Mehl, L. C., ... 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

Neutrophil-induced genomic instability impedes resolution of inflammation and wound healing. / Butin-Israeli, Veronika; Bui, Triet M.; Wiesolek, Hannah L.; Mascarenhas, Lorraine; Lee, Joseph J.; Mehl, Lindsey C.; Knutson, Kaitlyn R.; Adam, Stephen A.; Goldman, Robert D.; Beyder, Arthur; Wiesmuller, Lisa; Hanauer, Stephen B.; Sumagin, Ronen.

In: Journal of Clinical Investigation, Vol. 129, No. 2, 01.02.2019, p. 712-726.

Research output: Contribution to journalArticle

Butin-Israeli, V, Bui, TM, Wiesolek, HL, Mascarenhas, L, Lee, JJ, Mehl, LC, Knutson, KR, Adam, SA, Goldman, RD, Beyder, A, Wiesmuller, L, Hanauer, SB & Sumagin, R 2019, 'Neutrophil-induced genomic instability impedes resolution of inflammation and wound healing', Journal of Clinical Investigation, vol. 129, no. 2, pp. 712-726. https://doi.org/10.1172/JCI122085
Butin-Israeli V, Bui TM, Wiesolek HL, Mascarenhas L, Lee JJ, Mehl LC et al. Neutrophil-induced genomic instability impedes resolution of inflammation and wound healing. Journal of Clinical Investigation. 2019 Feb 1;129(2):712-726. https://doi.org/10.1172/JCI122085
Butin-Israeli, Veronika ; Bui, Triet M. ; Wiesolek, Hannah L. ; Mascarenhas, Lorraine ; Lee, Joseph J. ; Mehl, Lindsey C. ; Knutson, Kaitlyn R. ; Adam, Stephen A. ; Goldman, Robert D. ; Beyder, Arthur ; Wiesmuller, Lisa ; Hanauer, Stephen B. ; Sumagin, Ronen. / Neutrophil-induced genomic instability impedes resolution of inflammation and wound healing. In: Journal of Clinical Investigation. 2019 ; Vol. 129, No. 2. pp. 712-726.
@article{12c1feaefda24453a308d69987267c28,
title = "Neutrophil-induced genomic instability impedes resolution of inflammation and wound healing",
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",
year = "2019",
month = "2",
day = "1",
doi = "10.1172/JCI122085",
language = "English (US)",
volume = "129",
pages = "712--726",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "2",

}

TY - JOUR

T1 - Neutrophil-induced genomic instability impedes resolution of inflammation and wound healing

AU - Butin-Israeli, Veronika

AU - Bui, Triet M.

AU - Wiesolek, Hannah L.

AU - Mascarenhas, Lorraine

AU - Lee, Joseph J.

AU - Mehl, Lindsey C.

AU - Knutson, Kaitlyn R.

AU - Adam, Stephen A.

AU - Goldman, Robert D.

AU - Beyder, Arthur

AU - Wiesmuller, Lisa

AU - Hanauer, Stephen B.

AU - Sumagin, Ronen

PY - 2019/2/1

Y1 - 2019/2/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85060887997&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85060887997&partnerID=8YFLogxK

U2 - 10.1172/JCI122085

DO - 10.1172/JCI122085

M3 - Article

C2 - 30640176

AN - SCOPUS:85060887997

VL - 129

SP - 712

EP - 726

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 2

ER -