Neutrophil-induced genomic instability impedes resolution of inflammation and wound healing.
DNA repair
Gastroenterology
Inflammation
Inflammatory bowel disease
Neutrophils
Journal
The Journal of clinical investigation
ISSN: 1558-8238
Titre abrégé: J Clin Invest
Pays: United States
ID NLM: 7802877
Informations de publication
Date de publication:
01 02 2019
01 02 2019
Historique:
received:
11
05
2018
accepted:
20
11
2018
pubmed:
15
1
2019
medline:
18
12
2019
entrez:
15
1
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 30640176
pii: 122085
doi: 10.1172/JCI122085
pmc: PMC6355304
doi:
pii:
Substances chimiques
MIRN155 microRNA, human
0
MIRN23a microRNA, human
0
MicroRNAs
0
Mirn155 microRNA, mouse
0
Mirn23b microRNA, mouse
0
Reactive Oxygen Species
0
RAD51 protein, human
EC 2.7.7.-
Rad51 Recombinase
EC 2.7.7.-
Rad51 protein, mouse
EC 2.7.7.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
712-726Subventions
Organisme : NIDDK NIH HHS
ID : K01 DK101675
Pays : United States
Organisme : NIDDK NIH HHS
ID : K08 DK106456
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA060553
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK084567
Pays : United States
Commentaires et corrections
Type : CommentIn
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