Macrophages originate from the myeloid lineage and maintain tissue homeostasis, and repair as well as regulate the physiological inflammatory responses associat-ed with disease progression. Moreover, they are widely recognized for their adapt-able phenotypic changes in response to environmental as well as molecular cues which results in a broad phenotypic spectrum ranging from pro-inflammatory to immunosuppressive subtypes. Metabolic, hypoxic, and cytokine imbalance within the tissue microenvironment in response to cancer and atherosclerosis progres-sion, influences the phenotype of tissue-resident macrophages and infiltrating monocytes. Here, I generated and analyzed an in vitro model system to evaluate the effect of oleate-dependent polarization on macrophages. I identified that hu-man monocyte-derived macrophages when polarized in vitro in the presence of oleate, result in a novel macrophage phenotype. This is due to lipid accumulation, which harbors an active immunosuppressive transcriptional phenotype based on the expression of the transcription factors sXBP-1 and GATA3 transcription factors albeit downregulates the immunosuppressive scavenger receptors CD200R1, CD163. These macrophages do not modulate T-cell proliferation capacity indicat-ing an overall anergic immunosuppressive macrophage phenotype. These data emphasize the importance of increased lipid metabolism in macrophages and fur-ther identification of this phenotype in solid tumors and in atherosclerotic plaques. Herein I also reported that oleate-dependent murine bone marrow-derive macro-phages polarize into immunosuppressive TAM phenotype independent of IL-4 sig-naling. Additionally, I also generated a novel genetic mouse model to evaluate the role of DGAT1 & 2 enzymes in regulating myeloid cell phenotype. Initial investiga-tions based on oleate-dependent in vitro polarization of murine bone marrow-derived macrophages showed that the DGAT1 enzyme reduced lipid accumula-tion. Hence highlighting the importance of DGAT1 enzyme in regulating lipid drop-let formation associated with macrophage phenotype.
