Coenzyme A activates TLR4 and enhances alternative macrophage activation in line with MyD88 agonism
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.
Authors
- Angel A Cortez
- Anthony E. Jones (ORCID: https://orcid.org/0000-0003-2058-6021)
- Ajit S. Divakaruni (ORCID: https://orcid.org/0000-0002-2528-9651)
- Thomas G. Graeber (ORCID: https://orcid.org/0000-0001-8574-9181)
- Alexander Hoffmann (ORCID: https://orcid.org/0000-0002-5607-3845)
- Carolina Chávez
- Marisa Mekkittikul (ORCID: https://orcid.org/0000-0003-1739-9452)
- Nicholas Bayley (ORCID: https://orcid.org/0000-0003-0489-0592)
- Steven J. Bensinger (ORCID: https://orcid.org/0000-0002-9657-4206)
- Andréa B Ball (ORCID: https://orcid.org/0000-0002-8214-7190)
- Alessandro Sammarco (ORCID: https://orcid.org/0000-0003-1977-3292)
- Clarissa Carrillo
- Neira Ibrahimovic
- Richard L. Watson (ORCID: https://orcid.org/0000-0002-8931-9370)
- Wei Yuan Hsieh
- Amy Rios
- Natalie A. Falta (ORCID: https://orcid.org/0009-0004-7413-4527)
- Amber B Reyes
Institutions
- University of California, Los Angeles (US)
- UCLA Medical Center (US)
Publication Details
- Journal
- EMBO Reports
- Published
- 2026-09-18
- DOI
- https://doi.org/10.1038/s44319-026-00925-y
- Primary Topic
- Neurological diseases and metabolism
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- W. M. Keck Foundation
- Agilent Technologies
- National Heart, Lung, and Blood Institute
- National Cancer Institute
- National Institute of General Medical Sciences
- National Institute of Allergy and Infectious Diseases