Hypoxia-inducible Factors in Macrophage Polarization and Metabolic Reprogramming Under Stress: Implications for...

Hypoxia-inducible Factors (HIFs) are the transcriptional regulators of the cellular response to low oxygen tension and metabolic changes. The transition of macrophages and their adaptability to environmental stressors, such as hypoxia and nutrient deprivation, serve as the central regulators of immune responses. This review covers the role of Hypoxia-Inducible Factors (HIFs), chiefly HIF-1α and HIF-2α, in stress-mediated macrophage polarization and metabolic reprogramming. HIF-1α drives glycolytic activity and inflammatory gene expression, resulting in the development of an M1 - like pro-inflammatory activation state, while HIF-2α enables alternatively activated (M2- like) macrophages to support tissue remodeling, angiogenesis, and resolution of inflammation through oxidative metabolism and tissue repair. The two proteins HIF-1α and HIF-2α maintain a balance that controls whether macrophages develop inflammatory diseases or repair damaged tissues; therefore, this balance serves as a potential target for medical treatments. The balance between HIF-1α and HIF-2α determines how macrophages respond to inflammation versus tissue repair, representing a new area for potential treatment development. Additional modulation of these responses is achieved through interaction with the NF-κB, mTOR, and STAT3 signaling pathways. Any metabolic changes downstream of the HIFs can alter the functional outcome of macrophages in diseases such as obesity, cancer, atherosclerosis, and chronic inflammation. Inflammation resolution and angiogenesis, probably facilitated via HIFs, follow efficient wound healing and tissue regeneration. With the refinement in emerging technologies and future therapeutic opportunities in molecular technologies such as CRISPR and single-cell multi-omics, it has become possible to unravel the finely regulated, context-dependent roles of HIFs, thus opening exciting vistas for immune therapeutics.