Distinct role of FoxO1 in M‐CSF‐ and GM‐CSF‐differentiated macrophages contributes LPS‐mediated IL‐10: implication in hyperglycemia

Macrophages are a heterogeneous population of immune cells that are essential for the initiation and containment inflammation. There are 2 well‐established populations of inflammatory macrophages: classically activated M1 and alternatively activated M2 macrophages. The FoxO family of transcription factors plays key roles in a number of cellular processes, including cell growth, metabolism, survival, and inflammation. In this study, we determined whether the expression of FoxO1 contributes polarization of macrophages toward the M2‐like phenotype by enhancing IL‐10 cytokine expression. We identified that FoxO1 is highly expressed in M‐CSF‐derived (M2‐like) macrophage subsets, and this M2‐like macrophages showed a preferential FoxO1 enrichment on the IL‐10 promoter but not in GM‐CSF‐derived (M1‐like) macrophages during classic activation by LPS treatment, which suggests that FoxO1 enhances IL‐10 by binding directly to the IL‐10 promoter, especially in BMMs. In addition, our data show that macrophages in the setting of hyperglycemia contribute to the macrophage‐inflammatory phenotype through attenuation of the contribution of FoxO1 to activate IL‐10 expression. Our data identify a novel role for FoxO1 in regulating IL‐10 secretion during classic activation and highlight the potential for therapeutic interventions for chronic inflammatory conditions, such as atherosclerosis, diabetes, inflammatory bowel disease, and arthritis.