The metabolic cofactor Coenzyme A enhances alternative macrophage activation via MyD88-linked signaling [ATAC-seq]

Metabolites and metabolic co-factors can shape the innate immune response, though the pathways by which these molecules adjust inflammation remain incompletely understood. Here we show that the metabolic cofactor Coenzyme A (CoA) enhances IL-4 driven alternative macrophage activation [M(IL-4)] in vitro and in vivo. Unexpectedly, we found that perturbations in intracellular CoA metabolism did not influence M(IL-4) differentiation. Rather, we discovered that exogenous CoA is a weak TLR4 agonist which primes macrophages for increased receptivity to IL-4 signals and resolution of inflammation via MyD88. Mechanistic studies revealed MyD88- linked signals enhance IL-4 responsiveness, in part, by reshaping chromatin accessibility to enhance transcription of IL-4-linked genes. The results identify CoA as a host metabolic co-factor that influences macrophage function through an extrinsic TLR4-dependent mechanism and suggest that damage-associated molecular patterns (DAMPs) can prime macrophages for alternative activation and resolution of inflammation.