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

Neudecker, Viola, Haneklaus, Moritz, Jensen, Owen, Khailova, Ludmila, Masterson, Joanne C., Tye, Hazel, Biette, Kathryn, Jedlicka, Paul, Brodsky, Kelley S., Gerich, Mark E., Mack, Matthias, Robertson, Avril A. B., Cooper, Matthew A., Furuta, Glenn T., Dinarello, Charles A., O'Neill, Luke A., Eltzschig, Holger K., Masters, Seth L. and McNamee, Eoin N. (2017) Myeloid-derived miR-223 regulates intestinal inflammation via repression of the NLRP3 inflammasome. Journal of Experimental Medicine, 214 6: 1737-1752. doi:10.1084/jem.20160462


Author Neudecker, Viola
Haneklaus, Moritz
Jensen, Owen
Khailova, Ludmila
Masterson, Joanne C.
Tye, Hazel
Biette, Kathryn
Jedlicka, Paul
Brodsky, Kelley S.
Gerich, Mark E.
Mack, Matthias
Robertson, Avril A. B.
Cooper, Matthew A.
Furuta, Glenn T.
Dinarello, Charles A.
O'Neill, Luke A.
Eltzschig, Holger K.
Masters, Seth L.
McNamee, Eoin N.
Title Myeloid-derived miR-223 regulates intestinal inflammation via repression of the NLRP3 inflammasome
Journal name Journal of Experimental Medicine   Check publisher's open access policy
ISSN 0022-1007
1540-9538
Publication date 2017-06-01
Sub-type Article (original research)
DOI 10.1084/jem.20160462
Open Access Status Not yet assessed
Volume 214
Issue 6
Start page 1737
End page 1752
Total pages 16
Place of publication New York, NY, United States
Publisher Rockefeller University Press
Language eng
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.
Formatted 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.
Keyword Immunology
Immunology and Allergy
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID

R01-HL109233 | R01-DK082509 | R01-HL119837 | POI-HL114457 | K01DK106315 | R01 DK097075 | R01- HL098294 | R01-HL133900 | R01-DK109574

409992 | 3760 | 273007
1057815 | 361646 | 1099262


Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Institute for Molecular Bioscience - Publications
 
Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 3 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 4 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Sun, 16 Jul 2017, 02:11:18 EST by System User on behalf of Learning and Research Services (UQ Library)