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oai:repisalud.isciii.es:20.500.12105/273392026-03-21T01:17:08Zcom_20.500.12105_19586com_20.500.12105_2202col_20.500.12105_19587

00925njm 22002777a 4500 dc Dunphy, Gillian author Adán-Barrientos, Irene author Fernández-Delgado, Irene author Villarroya-Beltri, Carolina author Heras-Murillo, Ignacio author Moya-Ruiz, Elena author Sánchez-Álvarez, Miguel author Jarit-Cabanillas, Aitor author Del Pozo, Miguel A author Guerra, Susana author Sánchez-Madrid, Francisco author Sancho, David author 2026-02-10 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. Immunity. 2026 Feb 10;59(2):306-321. Immunity 41610845 https://hdl.handle.net/20.500.12105/27339 efferocytosis interferon-stimulated genes macrophage metabolism mitochondrial endoplasmic reticulum contacts mitochondrial fission mitochondrial membrane potential oxidative phosphorylation type I interferon viral infection A type I interferon-mitochondrial axis regulates efferocytosis and interferon-stimulated gene induction in macrophages.