MicroRNA-223 Suppresses the Canonical NF-kB Pathway in Basal Keratinocytes to Dampen Neutrophilic Inflammation

MicroRNA-223 is known as a myeloid-enriched anti-inflammatory microRNA that is dysregulated innumerous inflammatory conditions. Here, we report that neutrophilic inflammation (wound response) is augmented in miR-223-deficient zebrafish, due primarily to elevated activation of the canonical nuclear factor kB (NF-kB) pathway. NF-kB over-activation is restricted to the basal layer of the surface epithelium, although miR-223 is detected throughout the epithelium and in phagocytes. Not only phagocytes but also epithelial cells are involved in miR-223-mediated regulation of neutrophils’ wound response and NF-kB activation. Cul1a/b, Traf6, and Tab1 are identified as direct targets of miR-223, and their levels rise in injured epithelium lacking miR-223. In addition, miR-223 is expressed in cultured human bronchial epithelial cells, where it also downregulates NF-kB signaling. Together, this direct connection between miR-223 and the canonical NF-kB pathway provides a mechanistic understanding of the multi-faceted role of miR-223 and highlights the relevance of epithelial cells in dampening neutrophil activation.