MicroRNA-223 Suppresses the Canonical NF-κB Pathway in Basal Keratinocytes to Dampen Neutrophilic Inflammation
Wenqing Zhou,
Arpita S. Pal,
Alan Yi-Hui Hsu,
Theodore Gurol,
Xiaoguang Zhu,
Sara E. Wirbisky-Hershberger,
Jennifer L. Freeman,
Andrea L. Kasinski,
Qing Deng
Affiliations
Wenqing Zhou
Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA
Arpita S. Pal
Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA
Alan Yi-Hui Hsu
Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA
Theodore Gurol
Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA
Xiaoguang Zhu
Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA
Sara E. Wirbisky-Hershberger
School of Health Sciences, Purdue University, West Lafayette, IN 47907, USA
Jennifer L. Freeman
School of Health Sciences, Purdue University, West Lafayette, IN 47907, USA; Purdue University Center for Cancer Research, West Lafayette, IN 47907, USA
Andrea L. Kasinski
Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA; Purdue University Center for Cancer Research, West Lafayette, IN 47907, USA
Qing Deng
Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA; Purdue University Center for Cancer Research, West Lafayette, IN 47907, USA; Purdue Institute for Inflammation, Immunology, and Infectious Disease, West Lafayette, IN 47907, USA; Corresponding author
Summary: MicroRNA-223 is known as a myeloid-enriched anti-inflammatory microRNA that is dysregulated in numerous 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 κB (NF-κB) pathway. NF-κB 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-κB 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-κB signaling. Together, this direct connection between miR-223 and the canonical NF-κB pathway provides a mechanistic understanding of the multifaceted role of miR-223 and highlights the relevance of epithelial cells in dampening neutrophil activation.
