How IFN Signaling Tunes Macrophage Mitochondria in Inflammation Resolution

When our body fights an infection, the immune system must quickly activate defenses and trigger a beneficial inflammatory response. It’s just as important to be able to resolve that inflammation and return to homeostasis. Macrophages play a key role in this balance. These immune system cells specialize in phagocytosing, or engulfing, cells that have died due to viral infection and in repairing infection- or inflammation‑related tissue damage.

A preclinical study conducted at the Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) has now uncovered the mechanism by which a signal associated with antiviral and inflammatory responses—type I interferon (IFN‑I)—tunes macrophage mitochondria to enhance the clearance of tissue damage and prevent uncontrolled inflammation.

The results of their study, involving cells and animal models, could have future clinical utility, the investigators suggest. In their published paper in Immunity, the authors, including first author Gillian Dunphy, PhD, a researcher in the immunobiology group led by David Sancho PhD, head of the CNIC Immunobiology Laboratory, concluded, “Given the promise of IFN-I in clinical settings such as cancer, but its current lack of success, an increased understanding of metabolic adaptations downstream of IFNAR may help explain the multifunctional roles of this cytokine.” The team’s paper is titled “A type I interferon-mitochondrial axis regulates efferocytosis and interferon-stimulated gene induction in macrophages.”

Macrophages are innate immune cells required for mammalian development, homeostasis, and pathogen clearance, the authors explained. “They act as tissue sentinels, sensing pathogen- and damage-associated molecular patterns through pattern recognition receptors (PRRs). IFN‑I is a cytokine that can promote either inflammatory or anti‑inflammatory responses, depending on the disease context. It activates a specific inflammatory program known as interferon‑stimulated genes (ISGs). “IFN-I, comprising IFN-α and IFN-β are fundamental for immune system function,” the researchers further noted. “They signal via the interferon α/β receptor (IFNAR), inducing IFN-stimulated genes (ISGs).”

When kept in check, inflammation is beneficial, helping macrophages clean up dead cells and repair tissue damage, for example, during viral infections. The newly published study answers the question of how IFN‑I regulates macrophage function for inflammation resolution.

The CNIC team showed that when macrophages detect nucleic acids associated with viral infections inside the cell, they change their metabolism. The cells’ mitochondria lower the mitochondrial membrane potential (MMP) but continue to function properly.

This change occurs through the production of IFN‑I in response to viral infection, which binds to the IFN‑I receptor on the macrophage and triggers the production of the ISG protein ISG15. ISG15, the authors explained, is a ubiquitin-like protein that has been implicated in antiviral immunity as well as the modulation of cellular metabolism. “The timely induction of IFNs and ISGs is essential for pathogen clearance and the resolution of inflammation,” they wrote.

Low MMP is often associated with mitochondrial malfunction or damage, the investigators commented, but their newly reported study results suggest that it may be associated with increased ATP synthesis. “We found that a specific interferon‑stimulated protein, called ISG15, binds to mitochondrial proteins and provokes two coordinated changes: increased ATP production and a reduction in mitochondrial membrane potential,” Dunphy noted. “These metabolic changes in macrophages improve their ability to remove dead cells, which helps inflammation resolution … In addition, the drop in mitochondrial membrane potential activates a protease that increases mitochondrial fragmentation. This reshapes metabolism and reduces the expression of inflammatory genes, so that IFN‑I itself promotes the resolution of inflammation.”

As part of their study, the researchers combined metabolic analyses, advanced microscopy, and work in cellular and animal models. They observed that treatment with IFN‑I increases macrophage uptake of apoptotic cells—efferocytosis—and that this improvement disappears in the absence of ISG15. “They also found that changes in mitochondrial shape and communication act as a natural regulator that prevents excessive interferon signaling—something that, in other contexts, is associated with autoinflammation. “Collectively, these observations suggest a feedback loop upon IFN-I detection to limit ISG induction and promote clearance of cellular debris,” the authors concluded in their report.

Sancho further commented, “This finding maps out a new way in which antiviral signals engage with cellular metabolism to balance defense and repair. Understanding and modulating this axis could inspire strategies to accelerate the resolution of inflammation in different pathologies or to fine‑tune interferon‑based treatments, maximizing benefits while minimizing undesired effects.”

The study was conducted in collaboration with research teams led by Susana Guerra (Universidad Autonoma de Madrid) and Francisco Sanchez-Madrid (La Princesa, Madrid).

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