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Macrophages are highly plastic cells, which play key roles in the innate immune system. In response to signals associated with microbial infection such as lipopolysaccharide (LPS) and interferon (IFN)-γ, macrophages transition through multiple functional states allowing for a timely mounting and resolution of inflammation. In this work, we show that these functional transitions in response to LPS+ IFNγ stimulation are accompanied by dynamic changes in metabolism. In particular, macrophages exhibit dynamic alteration in the abundance of key immunomodulatory metabolites derived from the TCA cycle. This work identifies inhibition of the TCA cycle enzymes, pyruvate dehydrogenase complex (PDHC) and oxoglutarate dehydrogenase complex (OGDC), as an important driver of these changes during later stages of the response to stimulation. Inhibition of these structurally related enzymes is largely driven by nitric …