GATA2 Induces a Stem Cell-Like Transcriptional Program in Macrophages that Promotes Atherogenesis

Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipid-laden necrotic macrophages within blood vessels walls. GATA2 is a normally hematopoietic transcription factor which in the bone marrow helps maintain the proliferative, non-differentiated phenotype of hematopoietic progenitors. Unexpectedly, GATA2 is upregulated in macrophages within atherosclerotic plaque, where it plays an unknown role in disease progression. Although GATA2 can be expressed from two promoters, we determined that the atherogenic stimuli oxidized low-density lipoprotein and TNFα induce GATA2 expression via the internal (IG) GATA2 promoter, with GATA2 transcription initiated by the transcription factors NF-κB, STAT1, and the aryl hydrocarbon receptor. GATA2 had a divergent effect on promoter activity, with GATA2 upregulating genes associated with stem cell maintenance, proliferation, reactive oxygen species production, and migration, while downregulating genes central to macrophage function including those for cholesterol efflux, pathogen phagocytosis, and for the efferocytosis of apoptotic cells. Consequentially, GATA2-expressing macrophages had a pro-atherogenic phenotype typified by an invasive phenotype, poor cholesterol efflux, and impaired phagocytosis and efferocytosis. These results indicate that GATA2 upregulation induces an immature, stem cell-like phenotype in atheroma macrophages, thereby promoting plaque cellularity while compromising atheroprotective mechanisms such as cholesterol clearance and apoptotic cell removal.