Macrophage-KLF6 signaling promotes experimental atherogenesis
Cardiovascular disease accounts for one in every four deaths in the United States and is the single largest cause of mortality around the world.  The most common cause of cardiovascular-related deaths are due to development of occlusive atherosclerotic plaques. A hallmark event in the development of atherosclerotic plaque is the accumulation of lipid-laden macrophages in the subendothelial layers of affected blood vessels.  Macrophages are key players in all stages of atherogenesis, including plaque initiation, growth, rupture, as well as healing of ruptured plaques. In this context, macrophages are the principal innate immune cells that modulate atherogenesis by engaging in various processes such as inflammation, extracellular matrix degradation, phagocytosis, and efferocytosis. Here, we report that macrophage Kruppel-like factor 6 (KLF6) deficiency attenuates pro-inflammatory gene expression and experimentally induced atherosclerotic plaque development. Our in vivo studies show that myeloid-KLF6 deficiency on Apoe-null background significantly curtails high-fat/high-cholesterol diet-induced atherosclerotic lesion formation and macrophage abundance in atherosclerotic plaques.  Integrated transcriptomics and Gene Set Enrichment Analysis show that KLF6 deficiency significantly attenuates a large number of TNF-induced gene targets, and TNF-induced IFN? response, IFN? response, and inflammatory response signaling in macrophages. At the molecular level, KLF6 promotes IRF1 signaling to enhance TNF-induced pro-inflammatory gene expression in macrophages. Collectively, our analyses show that KLF6 promotes pro-inflammatory gene expression in macrophages and boosts experimentally induced atherosclerotic plaque formation in vivo. Overall design: Lyz2cre and Klf6fl/fl:Lyz2cre mice BMDMs were stimulated with 10ng/ml TNF for 6 hours. Total RNA samples were subjected to RNAseq analyses.