A type I interferon-mitochondrial axis regulates efferocytosis and interferon-stimulated gene induction in macrophages

  • Immunity. 2026 Feb 10;59(2):306-321.e7. doi: 10.1016/j.immuni.2025.12.010.
Gillian Dunphy  1 ,  Irene Adán-Barrientos  2 ,  Irene Fernández-Delgado  3 ,  Carolina Villarroya-Beltri  4 ,  Ignacio Heras-Murillo  5 ,  Elena Moya-Ruiz  3 ,  Miguel Sánchez-Álvarez  6 ,  Aitor Jarit-Cabanillas  2 ,  Miguel A Del Pozo  5 ,  Susana Guerra  7 ,  Francisco Sánchez-Madrid  8 ,  David Sancho  9
Affiliations
  • 1. Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), 28029 Madrid, Spain. Electronic address: [email protected].
  • 2. Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), 28029 Madrid, Spain; Department of Immunology, Ophthalmology and ENT, School of Medicine, Universidad Complutense de Madrid, 28040 Madrid, Spain; Escuela de Doctorado, Universidad Autónoma de Madrid, 28049 Madrid, Spain.
  • 3. Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), 28029 Madrid, Spain; Escuela de Doctorado, Universidad Autónoma de Madrid, 28049 Madrid, Spain.
  • 4. Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), 28029 Madrid, Spain; Centro de Biología Molecular Severo Ochoa, CSIC, 28049 Madrid, Spain.
  • 5. Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), 28029 Madrid, Spain.
  • 6. Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), 28029 Madrid, Spain; Instituto de Investigaciones Biomédicas Sols-Morreale, CSIC-UAM, 28029 Madrid, Spain.
  • 7. Department of Preventive Medicine, Public Health and Microbiology, Universidad Autónoma de Madrid, 28029 Madrid, Spain.
  • 8. Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), 28029 Madrid, Spain; Instituto de Investigación Sanitaria Hospital Universitario La Princesa, Universidad Autónoma de Madrid, 28006 Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain.
  • 9. Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), 28029 Madrid, Spain. Electronic address: [email protected].
PMID: 41610845 DOI: 10.1016/j.immuni.2025.12.010
Abstract

Macrophage metabolism is intricately linked to cellular function. Contrasting with Toll-like Receptor (TLR) stimulation, cytosolic nucleic acid sensing induced a decrease in mitochondrial membrane potential (MMP) while maintaining mitochondrial respiration. Interferon α/β (IFN-I) receptor (IFNAR) signaling was necessary and sufficient for this metabolic response. IFNAR signaling induced interferon-stimulated gene 15 (ISG15) expression and ISGylation of mitochondrial proteins, including subunits of mitochondrial complex V, increasing ATP production and decreasing MMP, thus enhancing macrophage efferocytic capacity. Moreover, the IFNAR-ISG15-mediated drop in MMP activated the mitochondrial protease OMA1, inducing mitochondrial fission and decreasing endoplasmic reticulum-mitochondria communication, thus dampening IFN-stimulated gene (ISG) induction. Loss of ISG15 or OMA1 enhanced histone acetylation and ISG induction upon IFN-I stimulation, in a manner dependent on mitochondrial calcium uptake. This increase in ISG induction provided protection against acute viral infections. These data indicate that IFNAR-ISG15 signaling boosts efferocytosis while limiting ISG induction, thereby promoting the resolution of inflammation.

Keywords
efferocytosis; interferon-stimulated genes; macrophage; metabolism; mitochondrial endoplasmic reticulum contacts; mitochondrial fission; mitochondrial membrane potential; oxidative phosphorylation; type I interferon; viral infection.
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