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

Abstract

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). http://www.fasebj.org

Kruppel‐like factor 6 promotes macrophage inflammatory and hypoxia response

“…Our studies over the years have demonstrated that KLF6‐deficient myeloid cells exhibit diminished pro‐inflammatory activations and functions . However, whether macrophage KLF6 deficiency alters the global proinflammatory gene program following inflammatory agent exposure has not been examined.…”

“…Our studies over the years have demonstrated that KLF6deficient myeloid cells exhibit diminished pro-inflammatory activations and functions. [19][20][21][22] However, whether macrophage KLF6 deficiency alters the global proinflammatory gene program following inflammatory agent exposure has not been examined. To identify the broadly deregulated inflammatory gene targets and signaling pathways associated with KLF6 deficiency, we performed unbiased RNAseq analyses.…”

“…Studies from our laboratory have uncovered that KLF6 is predominantly expressed in cells of myeloid origin and KLF6 deficiency significantly attenuated inducible pro‐inflammatory gene expression in macrophages . At the molecular level, KLF6 robustly elevate pro‐inflammatory gene expression by promoting NFκB functions as well as repressing critical anti‐inflammatory genes such as PPARγ, BCL6, and miR‐223 expression in macrophages . More importantly, myeloid‐KLF6‐deficient mice are protected from chronic inflammatory disorders such as cutaneous inflammation, experimental models of colitis, high‐fat diet‐induced obesity, insulin resistance, and glucose intolerance .…”

“…19 At the molecular level, KLF6 robustly elevate pro-inflammatory gene expression by promoting NFκB functions as well as repressing critical anti-inflammatory genes such as PPARγ, BCL6, and miR-223 expression in macrophages. [19][20][21] More importantly, myeloid-KLF6-deficient mice are protected from chronic inflammatory disorders such as cutaneous inflammation, experimental models of colitis, high-fat diet-induced obesity, insulin resistance, and glucose intolerance. [19][20][21][22] In this context, whether myeloid-KLF6 regulate inflammatory and metabolic gene program has not been investigated.…”

“…[19][20][21] More importantly, myeloid-KLF6-deficient mice are protected from chronic inflammatory disorders such as cutaneous inflammation, experimental models of colitis, high-fat diet-induced obesity, insulin resistance, and glucose intolerance. [19][20][21][22] In this context, whether myeloid-KLF6 regulate inflammatory and metabolic gene program has not been investigated. In this study, we provide the evidence that KLF6 promotes broad innate immune cell inflammatory and hypoxic response gene programming by directly elevating HIF1α expression in macrophages.…”