Metabolic adaptation supports enhanced macrophage efferocytosis in limited-oxygen environments

Apoptotic cell clearance (efferocytosis), a process essential for organismal homeostasis, is performed by phagocytes that inhabit harsh tissue environments, including physiologic hypoxia. Here, we find macrophages, the predominant tissue-resident phagocyte, display enhanced efferocytosis under chronic hypoxia, characterized by increased internalization and accelerated degradation of apoptotic cells. Analysis of transcriptional and translational programs revealed that macrophages under chronic hypoxia induce two distinct states. The first, ‘primed’, state consists of concomitant induction of transcriptional and translational programs broadly associated with metabolism in naïve macrophages that persist during efferocytosis. The second, ‘poised’, state consists of transcription, but not translation, of phagocyte function programs in naïve macrophages that are subsequently translated during efferocytosis. We discovered that one such primed state consists of the efficient flux of glucose into a noncanonical pentose phosphate pathway (PPP) loop, whereby PPP-derived intermediates cycle back through the PPP to enhance production of NADPH. Mechanistically, we found that PPP activity directly supports enhanced efferocytosis activity under chronic hypoxia while simultaneously maintaining redox homeostasis. Thus, macrophages adapt to chronic hypoxia by adopting states that both support cell fitness and ensure ability to rapidly and safely perform essential homeostatic functions.