Deciphering the Redox-Mediated Interplay Along the Gut–Lung–Brain Axis: Macrophage and Microglia Hyperactivation in Systemic Inflammation

Emerging paradigms in systemic immunology have illuminated the intricate, bidirectional communication networks linking distant organ systems, which are conceptualized as the gut–lung–brain axis. The homeostasis of this anatomical triad is primarily disrupted by localized and systemic oxidative stress, which serves as a potent driver of chronic inflammatory cascades. This comprehensive narrative review comprehensively delineates the redox-sensitive molecular cross-talk between peripheral tissue-resident macrophages (alveolar and intestinal) and central nervous system microglia. Environmental insults or microbial dysbiosis trigger the overproduction of reactive oxygen species (ROS), which compromise epithelial and endothelial barrier integrity, thereby allowing inflammatory mediators to breach the blood–brain barrier and trigger neuroinflammation. Herein, we systematically evaluate the mechanistic evidence demonstrating how this systemic redox disequilibrium drives coordinated myeloid hyperactivation. Rather than operating as isolated cellular responses, peripheral macrophage activation establishes a self-perpetuating feedback loop that systematically lowers the activation threshold of central microglia. We focus on the molecular convergence of the classical nuclear factor kappa B (NF-κB) pathway and the NOD-like receptor protein 3 (NLRP3) inflammasome within these myeloid lineages, which orchestrates the transcription of cytotoxic cytokines and gasdermin D-mediated pore formation. Crucially, within the architecture of systemic immunology, baseline intracellular ROS production serves as an essential physiological redox signaling molecule requisite for maintaining homeostatic cellular responses, whereas the transition into unmitigated pathological oxidative distress acts as the primary orchestrator of multi-organ barrier collapse. To counteract this multi-organ deterioration, we highlight the translational and therapeutic potential of well-characterized antioxidant phytochemicals—acting as multi-target molecular rheostats capable of neutralizing free radical bursts, rescuing barrier junctions, and systematically reprogramming hyperactive myeloid phenotypes. Furthermore, this review examines the progressive functional impairment and exhaustion of the endogenous cytoprotective Nrf2/HO-1 signaling axis, which functions as the primary molecular rheostat failure under persistent and unmitigated oxidative distress. Finally, we address the strategic implementation of advanced biomimetic multi-organ-on-a-chip technologies designed to model this intercellular dialog, establishing a robust conceptual framework for understanding multi-organ inflammatory decay driven by synchronized macrophage and microglia hyperactivation.