OutFOXing Myeloid Cells in Atherosclerosis With FoxOs
Compelling experimental and human studies implicate myeloid-driven inflammation as a significant component in the initiation and progression of atherosclerosis and a range of other chronic inflammatory diseases, including obesity, type 2 diabetes mellitus, and metabolic syndrome. Indeed, elevated circulating white blood cell (WBC) count is a strong predictor of coronary heart disease and all-cause mortality independent of traditional risk factors, an association that has been observed across sexes, age, and diverse ethnic populations over the past 4 decades.1,2 Elevated monocyte counts may also correlate with cardiovascular risk better than other WBC subsets.3 Accumulating studies have recognized specific circulating myeloid cells, such as Ly-6C+ monocytes in mice and CD14+CD16+ subsets in humans, as potential instigators of atherosclerotic lesion formation and insulin resistance.4 The importance of the number of peripheral monocytic cells as a contributor to lesion formation was highlighted, in part, using op/op mice that bear a mutation in the coding region for macrophage colony-stimulating factor; op/op mice bred onto atherosclerotic-prone mice exhibited marked reductions in lesion formation.5 Subsequent experimental studies demonstrated that reduction in the number of peripheral myeloid cells in the circulation pharmacologically also attenuated the development of vascular inflammatory disease.6 However, identification of the downstream transcriptional regulators that govern peripheral myeloid cell numbers and function in the context of atherosclerosis remain poorly understood.
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In this issue of Circulation Research, Tsuchiya7 reveals an important role for the forkhead box O (FoxO) family of transcription factors, namely FoxO1, FoxO3a, and FoxO4, in controlling the number of circulating myeloid cells and effects on atherosclerosis and insulin resistance. Specifically, myeloid ablation of all 3 FoxO isoforms increased the proliferation rate of granulocyte-macrophage progenitors (GMPs) in the bone marrow, resulting in elevated peripheral numbers of monocytes …