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 degradation of ACs. Transcriptional and translational analyses revealed that chronic physiological hypoxia induces two distinct but complimentary states. The first, “primed” state, consists of concomitant transcription and translation of metabolic programs in AC-naive macrophages that persist during efferocytosis. The second, “poised” state, 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.

凋亡细胞 (AC) 清除（胞吞作用）是由居住在恶劣生理环境中的吞噬细胞（例如巨噬细胞）执行的。在这里，我们发现巨噬细胞在长期（慢性）生理性缺氧下表现出增强的胞吞作用，其特征是 AC 的内化增加和加速降解。转录和翻译分析表明，慢性生理性缺氧会诱导两种不同但互补的状态。第一种状态是“启动”状态，由 AC 幼稚巨噬细胞中代谢程序的伴随转录和翻译组成，这些程序在胞吞作用期间持续存在。第二种，“平衡”状态，由 AC 幼稚巨噬细胞中吞噬细胞功能程序的转录（但不翻译）组成，这些程序在胞吞作用期间被翻译。从机制上讲，巨噬细胞有效地将葡萄糖转移到非典型戊糖磷酸途径 (PPP) 环中，以增强 NADPH 的产生。 PPP 衍生的 NADPH 通过确保吞噬溶酶体成熟和氧化还原稳态，直接支持生理缺氧下增强的胞吞作用。因此，处于生理性缺氧状态下的巨噬细胞会采取支持细胞健康的状态，并确保快速、安全地发挥基本的稳态功能。