Macrophage Adaptation to Hypoxia: Metabolism, Migration, and Phagocytosis

Lu Yuan^1,2*Tiemen Mellema¹Gésinda I. Geertsema-Doornbusch¹Henny C Van Der Mei^1*

• ¹University Medical Center Groningen, Groningen, Netherlands
• ²Universitair Medisch Centrum Groningen, Groningen, Netherlands

Background: Hypoxia is a hallmark of many diseases, including periodontitis, where it influences 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 physiologically relevant low oxygen tension (2% O₂) compared to normoxia (20% O₂), modulates macrophage metabolism, morphology, migration, and interaction with both commensal and pathogenic oral bacteria. Results: Hypoxia activated the 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 phagocytic capacity and effectively limited the intracellular proliferation of Streptococcus oralis and Porphyromonas gingivalis. Hypoxia also altered cytokine profiles, with increased IL-1β and IL-10, and reduced 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. Modulating these responses may inform novel therapeutic approaches targeting hypoxia-associated immune dysfunction.