Glucose Metabolism Dictates Murine Eosinophil Differentiation, Chemotaxis, and IL-4 Expression

Eosinophils express multiple hormone receptors and emerge as critical in the regulation of fat homeostasis and systemic metabolism. However, phenotypic and functional responses of naïve eosinophils to metabolic change are poorly understood. Here, we determined the acute and chronic effects of energy metabolism disruption on murine eosinophil differentiation and function To study differentiation, murine bone marrow-derived eosinophils were cultured in normoglycemic [6 mM] or hyperglycemic [20 mM] conditions for 13 days in the presence of IL-5. To assess plasticity in phenotype and function, mature differentiated eosinophils were treated with glucose [20 mM], insulin [633.6 mcIU/ml] or GLUT4 glucose transport inhibitor indinavir [200 uM] for 24 hours. Multi-panel flow cytometry and qPCR were used to quantify eosinophil phenotypic markers (Lin, Sca1, Siglec-F, CD11c, CD34, ST2) and cytokines (IL-4, IL-5, IL-10). We also quantified eosinophil chemotaxis in different glycemic conditions. Terminal IL-5-driven eosinophil proliferation, differentiation, and maturation were suppressed in hyperglycemic conditions. IL-4 expression was significantly induced in eosinophils in both acute and chronic hyperglycemia, but acutely suppressed in insulin- and indinavir-treated cells. Siglec-F expression was significantly reduced in mature indinavir-treated eosinophils compared to controls (from an average of 76% to 50%). Moreover, hyperglycemia significantly suppressed eosinophil chemotaxis to eotaxin (CCL11). Differentiation, chemotaxis, and IL-4 expression in eosinophils are all sensitive to glucose levels in the environment. Disrupted glucose metabolism may be a linking factor for eosinophil responses in obesity, asthma, and inflammation.