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

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-223limits intestinal inflammation by constraining the nlrp3 inflammasome. miR-223was increased in intestinal biopsies from patients with active IBD and in preclinical models of intestinal inflammation. miR-223mice presented with exacerbated myeloid- driven experimental colitis with heightened clinical, histopathological, and cytokine readouts. Mechanistically, enhanced NLRP3 inflammasomeexpression with elevated IL-1β was a predominant feature during the initiation of colitis with miR-223deficiency. Depletion of CCR2inflammatory monocytes and pharmacologic blockade of IL-1β or NLRP3 abrogated this phenotype. Generation of a novel mouse line, with deletion of the miR-223binding site in the NLRP3 3' untranslated region, phenocopiedthe characteristics of miR-223mice. Finally, nanoparticle-mediated overexpression of miR-223attenuated experimental colitis, NLRP3 levels, and IL-1β release. Collectively, our data reveal a previously unappreciated role for miR-223in regulating the innate immune response during intestinal inflammation.