Neudecker, Viola and Haneklaus, Moritz and Jensen, Owen and Khailova, Ludmila and Masterson, Joanne C. and Tye, Hazel and Biette, K.A. and Jedlicka, Paul and Brodsky, Kelley S. and Gerich, Mark E. and Mack, Matthias and Robertson, Avril A.B and Cooper, Matthew A. and Furuta, Glenn T. and Dinarello, Charles A. and O’Neill, Luke A. and Eltzschig, Holger K. and Masters, Seth L. and McNamee, Eóin N. (2017) Myeloid-derived miR-223 regulates intestinal inflammation via repression of the NLRP3 inflammasome. Journal of Experimental Medicine, 214 (6). p. 1737. ISSN 0022-1007

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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.

Item Type:	Article
Keywords:	Medicine, Research & Experimental; Cells; Activation; IL-1 Ulcerative-Colitis; In-vivo; IL-1-Beta; Colon; Immunology; Microrna Expression; Bowel-Disease; Dextran Sulfate; Inflammation - pathology; Inflammasomes - metabolism; Antibodies - metabolism; Nanoparticles - chemistry; Colitis - genetics; Humans, Middle Aged; Colitis - pathology; MicroRNAs - metabolism; Monocytes - metabolism; Hematopoiesis; Interleukin-1beta - metabolism; Base Sequence; Colitis - chemically induced; Inflammatory Bowel Diseases - pathology; Inflammatory Bowel Diseases - genetics; Adult; Neutrophils - metabolism; Disease Susceptibility; Intestines - pathology; NLR Family; Pyrin Domain-Containing 3 Protein - metabolism; Mice, Inbred C57BL; Mice; Knockout; Receptors; CCR2 - metabolism; Animals; Inflammation - genetics; Myeloid Cells - metabolism; MicroRNAs - genetics; 311; 319;
Academic Unit:	Faculty of Science and Engineering > Biology
Item ID:	11660
Identification Number:	https://doi.org/10.1084/jem.20160462
Depositing User:	Eoin McNamee
Date Deposited:	12 Nov 2019 12:07
Journal or Publication Title:	Journal of Experimental Medicine
Publisher:	Rockefeller University Press
Refereed:	Yes
URI:	Publisher
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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