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

V Neudecker, M Haneklaus, O Jensen… - Journal of Experimental …, 2017 - rupress.org
V Neudecker, M Haneklaus, O Jensen, L Khailova, JC Masterson, H Tye, K Biette, P Jedlicka…
Journal of Experimental Medicine, 2017rupress.org
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 …
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.
rupress.org