Metabolic adaptation supports enhanced macrophage efferocytosis in limited-oxygen environments

Apoptotic cell (AC) clearance (efferocytosis) is performed by phagocytes, such as macrophages, that inhabit harsh physiological environments. Here, we find that macrophages display enhanced efferocytosis under prolonged (chronic) physiological hypoxia, characterized by increased internalization and accelerated degra-dation of ACs. Transcriptional and translational analyses revealed that chronic physiological hypoxia induces two distinct but complimentary states. The first, primedstate, consists of concomitant transcription and translation of metabolic programs in AC-naive macrophages that persist during efferocytosis. The second, poisedstate, consists of transcription, but not translation, of phagocyte function programs in AC-naive macrophages that are translated during efferocytosis. Mechanistically, macrophages efficiently flux glucose into a noncanonical pentose phosphate pathway (PPP) loop to enhance NADPH production. PPP-derived NADPH directly supports enhanced efferocytosis under physiological hypoxia by ensuring phagolysosomal maturation and redox homeostasis. Thus, macrophages residing under physiological hypoxia adopt states that support cell fitness and ensure performance of essential homeostatic functions rapidly and safely.

Automated summary

Research reveals that macrophages exhibit enhanced efferocytosis of apoptotic cells under prolonged physiological hypoxia, characterized by increased internalization and accelerated degradation. This is achieved through the noncanonical pentose phosphate pathway, which promotes NADPH production and ensures phagolysosomal maturation and redox homeostasis. This adaptation supports cell fitness and essential homeostatic functions.