Kruppel‐like factor 6 and miR‐223 signaling axis regulates macrophage‐mediated inflammation

Macrophage-mediated inflammation is an explicitly robust biologic response that plays a critical role in maintaining tissue homeostasis by eliminating deleterious agents. These tissue macrophages tailor appropriate responses to external cues by altering inflammatory gene expression. Therefore, transcription factors and regulators that modulate inflammatory gene expression play an essential role in shaping the macrophage inflammatory response. Here, we identify that Kruppel-like factor (KLF)6 promotes inflammation by restraining microRNA-223 (miR-223) expression in macrophages. We uncovered that pro- and anti-inflammatory agents oppositely regulate KLF6 and miR-223 expression in macrophages. Using complementary gain- and loss-of-function studies, we observed that overexpression of KLF6 attenuates and deficiency of KLF6 elevates miR-223 expression in macrophages. Furthermore, heightened miR-223 expression in KLF6-deficient macrophages significantly attenuates inducible proinflammatory gene expression. Concordantly, myeloid-KZ/6 deficiency significantly curbs diet-induced adipose tissue inflammation, obesity, glucose intolerance, and insulin resistance. At the molecular level, KLF6 directly represses miR-223 expression by occupying its promoter region. More importantly, genetic inhibition of miR-223-3P in KLF6-deficient macrophages completely reversed attenuated proinflammatory gene expression in macrophages. Collectively, our studies reveal that KLF6 promotes proinflammatory gene expression and functions by repressing miR-223 expression in macrophages.—Kim, G.-D., Ng, H. P., Patel, N., Mahabeleshwar, G. H. Kruppel-like factor 6 and miR-223 signaling axis regulates macrophage-mediated inflammation. FASEB J. 33, 10902–10915 (2019). www.fasebj.org