Control of Macrophage Activation by Coenzyme A

Abstract

Macrophages are innate immune cells responsible for processes as varied as killing pathogens, initiating wound-healing programs, and presenting antigens to T cells. To achieve this broad range of functions, they acquire pro- or anti-inflammatory programs (or ‘polarize’) by integrating intrinsic, extrinsic, and environmental signals. It is now well established that metabolic changes are critical for this process, though it remains unclear precisely which metabolic alterations are essential for (rather than merely being associated with) activation. Pro-inflammatory macrophage polarization with lipopolysaccharide (LPS) collapses mitochondrial ATP production. This profound decrease in oxidative phosphorylation is associated with increases in glycolysis, signaling metabolites from the TCA cycle, and mitochondrially derived redox signals. Conversely, anti-inflammatory activation with interleukin-4 (IL-4) is associated with substantial increases in oxidative phosphorylation and fatty acid oxidation (FAO). Previous work in our laboratory has shown that although FAO and mitochondrial ATP production are strongly associated with the IL-4 response, these are surprisingly dispensable, whereas coenzyme A homeostasis is obligatory [PMCID: PMC6125190]. This presentation will cover our current understanding of the essential metabolic requirements for anti-inflammatory macrophage activation, with a focus on the potential mechanisms by which coenzyme A may control the IL-4 response.