The metabolic cofactor Coenzyme A enhances alternative macrophage activation via MyD88-linked signaling

Author:

Jones Anthony E.,Rios Amy,Ibrahimovic Neira,Chavez Carolina,Bayley Nicholas A.,Ball Andréa B.,Hsieh Wei Yuan,Sammarco Alessandro,Bianchi Amber R.,Cortez Angel A.,Graeber Thomas G.ORCID,Hoffmann Alexander,Bensinger Steven J.,Divakaruni Ajit S.ORCID

Abstract

ABSTRACTMetabolites 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 vitroandin vivo. Unexpectedly, we found that perturbations in intracellular CoA metabolism did not influence m(IL-4) differentiation. Rather, we discovered that exogenous CoA provides a weak TLR4 signal which primes macrophages for increased receptivity to IL-4 signals and resolution of inflammation via MyD88. Mechanistic studies revealed MyD88-linked signals prime for 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 suggests that damage-associated molecular patterns (DAMPs) can prime macrophages for alternative activation and resolution of inflammation.

Publisher

Cold Spring Harbor Laboratory

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