GSE193294
An Unexpected Role for Acetyl Coenzyme A Carboxylase in Metabolic Control of the Macrophage Acute Inflammatory Response
Macrophages must rapidly shift their cellular metabolism to facilitate the induction of the proinflammatory response, including activation of lipid synthesis pathways. However, the links between lipid metabolism and polarization in response to inflammatory signals remains unclear. Acetyl-CoA Carboxylase (ACC) is central to lipid synthesis, cellular energy utilization, and acetylation-dependent enzyme activation, but its role in macrophages remains unclear. To interrogate the role of ACC in the inflammatory response, we generated myeloid-specific LysMCre Acacafl/fl Acacbfl/fl ACC double knockout (ACC?LysM) mice. Unexpectedly, myeloid-specific deletion or pharmacological inhibition of ACC attenuated lipopolysaccharide (LPS)-induced inflammation in mice, with decreased gene expression and protein levels of the proinflammatory cytokines IL-6 and IL-1?. Using in vitro transcriptomics, lipidomics, and bioenergetics approaches we find that ACC deletion reestablishes the metabolic setpoint in macrophages and is required for metabolic rewiring in response to LPS- but not IL-4-dependent signaling. This translated to blunted phenotypic polarization to proinflammatory but not alternatively activating stimuli. Mechanistically, we identified that the metabolic rewiring that results from ACC deletion increased basal acetylation at histone H3 lysine 27 (H3K27Ac), a marker of active enhancers, which was reduced in response to LPS in ACC-deficient BMDMs. The failure of macrophages lacking ACC to adapt their glycolytic metabolism and polarize to inflammatory stimuli impaired macrophage proinflammatory effector functions. Taken together these data identify a novel role for ACC in metabolic and transcriptional regulation of the acute inflammatory response. Overall design: Bone marrow-derived macrophages (BMDMs) from four male Acaca loxp/loxp Acacb loxp/loxp (flox control) and four male LysM-Cre Acaca loxp/loxp Acacb loxp/loxp (ACCLysM ACC1/ACC2 deficient) mice were stimulated with LPS (100ng/mL) for 6 hours and total RNA isolated for RNAseq