The metabolic modulator metformin affects the activation and survival of murine dendritic cell subsets

Abstract Unique immunometabolic pathways control the ability of dendritic cell subsets to activate, and metabolic modulators are proposed as therapeutic candidates in cancer and autoimmunity, although their effects on specific immune cells are not fully known. The metabolic inhibitor metformin, the first-choice oral treatment for type II diabetes, has many effects on immunometabolism, including the inhibition of complex I of oxidative phosphorylation. Metformin was shown to decrease the severity of autoimmunity in murine models by inhibiting the activation of T cells. Moreover, it can diminish tumor growth through affecting the polarization of tumor-infiltrating macrophages. Here, we determined the effects of metformin on three subsets of dendritic cells that are proposed to have different energy requirements for activation. Upon TLR stimulation, we found that metformin does not affect the activation of the inflammatory GM-CSF-dependent dendritic cells (iDCs) or the Flt3-L-dependent conventional dendritic cells (cDCs), which rely on an immuno-metabolic shift to glycolysis to fully activate and express costimulatory molecules and pro-inflammatory cytokines, but it decreased cDC survival at resting state. In contrast, we found that metformin inhibited the activation of plasmacytoid dendritic cells (pDCs), which requires both an increase in oxidative phosphorylation and glycolysis for activation. Our studies provide a new layer of complexity in the potential of metformin as treatment in autoimmunity and cancer by showing that this drug can inhibit the activation of pDCs and also eliminate resting cDCs, therefore altering in opposite directions the impact of these innate cell subsets on the immune response.