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Peer-reviewedCC BYEMBO Reports

Coenzyme A activates TLR4 and enhances alternative macrophage activation in line with MyD88 agonism

  • Anthony E Jones1
  • Amy Rios1
  • Neira Ibrahimovic1
  • Andréa B Ball1
  • Carolina Chavez1
  • Nicholas A Bayley1
  • Natalie A Falta1
  • Marisa Mekkittikul1
  • Clarissa Carrillo1
  • Wei Yuan Hsieh2
  • Alessandro Sammarco2
  • Amber B Reyes1
6 more authors
  • Angel A Cortez1
  • Thomas G Graeber1
  • Richard L Watson3
  • Alexander Hoffmann2
  • Steven J Bensinger2
  • Ajit S Divakaruni1
  1. 1Departments of Molecular and Medical Pharmacology, University of California
  2. 2Microbiology, Immunology, and Molecular Genetics, University of California
  3. 3Medicine, Division of Pulmonary and Critical Care Medicine; University of California
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Abstract

Metabolites and metabolic cofactors 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 find that perturbations in intracellular CoA metabolism do not influence M(IL-4) differentiation. Rather, we discover 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 reveal 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.

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Cite

BibTeXRIS
BibTeX
@article{jones2026coenzyme,
  title = {{Coenzyme A activates TLR4 and enhances alternative macrophage activation in line with MyD88 agonism}},
  author = {Anthony E Jones and Amy Rios and Neira Ibrahimovic and Andréa B Ball and Carolina Chavez and Nicholas A Bayley and Natalie A Falta and Marisa Mekkittikul and Clarissa Carrillo and Wei Yuan Hsieh and Alessandro Sammarco and Amber B Reyes and Angel A Cortez and Thomas G Graeber and Richard L Watson and Alexander Hoffmann and Steven J Bensinger and Ajit S Divakaruni},
  journal = {EMBO Reports},
  year = {2026},
  month = sep,
  doi = {10.1038/s44319-026-00925-y},
  url = {https://doi.org/10.1038/s44319-026-00925-y},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Coenzyme A activates TLR4 and enhances alternative macrophage activation in line with MyD88 agonism
AU  - Anthony E Jones
AU  - Amy Rios
AU  - Neira Ibrahimovic
AU  - Andréa B Ball
AU  - Carolina Chavez
AU  - Nicholas A Bayley
AU  - Natalie A Falta
AU  - Marisa Mekkittikul
AU  - Clarissa Carrillo
AU  - Wei Yuan Hsieh
AU  - Alessandro Sammarco
AU  - Amber B Reyes
AU  - Angel A Cortez
AU  - Thomas G Graeber
AU  - Richard L Watson
AU  - Alexander Hoffmann
AU  - Steven J Bensinger
AU  - Ajit S Divakaruni
PY  - 2026
DA  - 2026/09/01
JO  - EMBO Reports
DO  - 10.1038/s44319-026-00925-y
UR  - https://doi.org/10.1038/s44319-026-00925-y
AB  - Metabolites and metabolic cofactors 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 find that perturbations in intracellular CoA metabolism do not influence M(IL-4) differentiation. Rather, we discover 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 reveal 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.
SN  - 1469-3178
ER  -