Macrophage adaptation to hypoxia: metabolism, migration, and phagocytosis

Background Hypoxia is a hallmark of many diseases, including periodontitis, where it influences the immune cell behavior. In low-oxygen conditions, macrophages shift toward glycolytic metabolism, altering their phenotype and function, However, it remains unclear how these functional changes affect the interaction between macrophages and oral bacteria in the hypoxic environment of infectious tissue. Methods In this study, which focused on periodontitis, we addressed this gap by investigating how a physiologically relevant low oxygen tension (2% O 2 ) compared with normoxia (20% O 2 ) modulates the metabolism, morphology, migration, and interaction of macrophages with both commensal and pathogenic oral bacteria. Results Hypoxia activated the hypoxia-inducible factor-1 alpha (HIF-1α) signaling pathway, induced glycolytic metabolism, reduced proliferation, and led to a rounded morphology with amoeboid migration characteristics. Despite reduced mobility, hypoxic macrophages maintained their phagocytic capacity and effectively limited the intracellular proliferation of Streptococcus oralis and Porphyromonas gingivalis . Hypoxia also altered the cytokine profiles, with increased interleukin-1 beta (IL-1β) and IL-10, reduced tumor necrosis factor alpha (TNF-α), and enhanced reactive oxygen species production. Conclusion These findings highlight the plasticity of macrophages in adapting to low-oxygen environments and underscore their potential role in host defense and inflammation resolution in periodontal disease. The modulation of these responses may inform novel therapeutic approaches targeting hypoxia-associated immune dysfunction.