Redox signaling in innate immunity and inflammation: focus on macrophages and neutrophils

Redox signaling plays a central role in regulating macrophage and neutrophil function, integrating reactive oxygen species (ROS), reactive nitrogen species (RNS), and reactive sulfur species (RSS) to modulate innate immune responses. Reactive species modulate diverse cellular processes in phagocytes, including differentiation, metabolic adaptation, cytokine production, and cell death. Antioxidant systems, including the glutathione and thioredoxin systems, play essential roles in maintaining redox balance, counteracting excessive oxidants, and preserving immune cell function. Oxidative post-translational modifications of proteins, mainly on cysteine and methionine residues, act as redox switches that regulate innate immune cell function. Dynamic redox modifications critically influence phagocyte metabolism, migration, phagocytosis, survival and communication with neighboring immune and non-immune cells, thereby controlling the response to infection as well as initiation and resolution of inflammation. Additionally, other oxidized mediators, such as oxidized mitochondrial DNA and oxidized lipids, contribute to immune regulation and its dysregulation in inflammatory diseases. Thus, redox signaling is tightly linked to both immune homeostasis and pathological inflammation. This review explores the mechanistic basis of redox regulation in macrophages and neutrophils, emphasizing the interplay between ROS, RNS, RSS and antioxidant defenses. We also discuss recent insights into the role of redox regulation in the context of pulmonary infection and inflammation. Overall, a deeper understanding of these redox-regulated pathways may reveal novel strategies for selectively modulating inflammation while preserving essential immune functions.