The IFN-γ-inducible GTPase IIGP1 regulates mitochondrial remodeling and immunometabolic reprogramming during inflammatory macrophage polarization

Macrophages are key effector cells of the innate immune system that undergo dynamic polarization into functionally distinct phenotypic states, ranging from classically activated inflammatory (M1) to alternatively activated (M2) macrophages. Inflammatory macrophage polarization requires coordinated integration of cytokine signaling, metabolic reprogramming, and mitochondrial remodeling. However, the molecular effectors that control inflammatory signaling for mitochondrial metabolism and remodeling remain poorly defined. Using quantitative mass spectrometry-based proteomics, we identified Interferon-inducible GTPase 1 (IIGP1) as one of the most robustly induced proteins during inflammatory macrophage polarization. Its expression is governed by the IFN-γ-JAK-STAT1 signaling axis and is crucial for this polarization process. IIGP1-deficient macrophages exhibited significantly impaired iNOS induction, nitric oxide production, pro-inflammatory gene expression, co-stimulatory surface marker expression, and morphological remodeling. Further, IIGP1 associates with mitochondria and its absence impairs key characteristics of inflammatory macrophages, including glycolytic metabolic reprogramming, mitochondrial redox adaptation, membrane potential regulation, and structural remodeling. Consistent with these defects, IIGP1-deficient macrophages displayed impaired intracellular killing of Escherichia coli and Salmonella Typhimurium. Collectively, these results point to IIGP1 as an IFN-γ-inducible effector that facilitates efficient inflammatory macrophage polarization and antibacterial immunity by linking inflammatory signaling to mitochondrial homeostasis and immunometabolic reprogramming.