Two-stage metabolic remodelling in macrophages in response to lipopolysaccharide and interferon-γ stimulation

In response to signals associated with infection or tissue damage, macrophages undergo a series of dynamic phenotypic changes. Here we show that during the response to lipopolysaccharide and interferon-γ stimulation, metabolic reprogramming in macrophages is also highly dynamic. Specifically, the tricarboxylic acid cycle undergoes a two-stage remodelling: the early stage is characterized by a transient accumulation of intermediates including succinate and itaconate, whereas the late stage is marked by the subsidence of these metabolites. The metabolic transition into the late stage is largely driven by the inhibition of the pyruvate dehydrogenase complex (PDHC) and the oxoglutarate dehydrogenase complex (OGDC), which is controlled by the dynamic changes in the lipoylation state of both PDHC and OGDC E2 subunits and phosphorylation of the PDHC E1 subunit. This dynamic metabolic reprogramming results in a transient metabolic state that strongly favours hypoxia-inducible factor-1α (HIF-1α) stabilization during the early stage, which subsides by the late stage; consistently, HIF-1α levels follow this trend. This study elucidates a dynamic and mechanistic picture of metabolic reprogramming in lipopolysaccharide and interferon-γ stimulated macrophages, and provides insights into how changing metabolism can regulate the functional transitions in macrophages over the course of an immune response. Macrophages engage in a sequence of dynamic functional changes during immune responses. Here the authors elucidate a two-stage remodelling of the tricarboxylic acid cycle during this process, which is driven by regulation of the pyruvate dehydrogenase and the oxoglutarate dehydrogenase complexes, and causes transient accumulation of immunoregulatory metabolites.