Format

Send to

Choose Destination
J Exp Med. 2017 Jun 5;214(6):1737-1752. doi: 10.1084/jem.20160462. Epub 2017 May 9.

Myeloid-derived miR-223 regulates intestinal inflammation via repression of the NLRP3 inflammasome.

Author information

1
Clinic for Anesthesiology, University Hospital of Ludwig-Maximilians-University, 80539 Munich, Germany.
2
Department of Anesthesiology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045.
3
School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
4
Mucosal Inflammation Program, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045.
5
Gastrointestinal Eosinophilic Disease Program, Section of Pediatric Gastroenterology, Hepatology, and Nutrition, Children's Hospital Colorado, Aurora, CO 80045.
6
Division of Inflammation, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
7
Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia.
8
Department of Pathology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045.
9
Division of Gastroenterology and Hepatology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045.
10
Department of Internal Medicine II, University Hospital Regensburg, 93053 Regensburg, Germany.
11
Institute for Molecular Bioscience, The University of Queensland, Brisbane City, QLD 4067, Australia.
12
Department of Medicine, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands.
13
Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045.
14
Department of Anesthesiology, University of Texas Medical School at Houston, Houston, TX 77030.
15
Mucosal Inflammation Program, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045 eoin.mcnamee@ucdenver.edu.

Abstract

MicroRNA (miRNA)-mediated RNA interference regulates many immune processes, but how miRNA circuits orchestrate aberrant intestinal inflammation during inflammatory bowel disease (IBD) is poorly defined. Here, we report that miR-223 limits intestinal inflammation by constraining the nlrp3 inflammasome. miR-223 was increased in intestinal biopsies from patients with active IBD and in preclinical models of intestinal inflammation. miR-223-/y mice presented with exacerbated myeloid-driven experimental colitis with heightened clinical, histopathological, and cytokine readouts. Mechanistically, enhanced NLRP3 inflammasome expression with elevated IL-1β was a predominant feature during the initiation of colitis with miR-223 deficiency. Depletion of CCR2+ inflammatory monocytes and pharmacologic blockade of IL-1β or NLRP3 abrogated this phenotype. Generation of a novel mouse line, with deletion of the miR-223 binding site in the NLRP3 3' untranslated region, phenocopied the characteristics of miR-223-/y mice. Finally, nanoparticle-mediated overexpression of miR-223 attenuated experimental colitis, NLRP3 levels, and IL-1β release. Collectively, our data reveal a previously unappreciated role for miR-223 in regulating the innate immune response during intestinal inflammation.

PMID:
28487310
PMCID:
PMC5460990
DOI:
10.1084/jem.20160462
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center