Efferocytosis and other corpse clearance transfers metal micronutrients to engulfing macrophages triggering a metallothionein response necessary to preserve mitochondrial function

In the human body, billions of cells die each day during normal turnover, infection, and tissue damage. Macrophages are critical for engulfing and clearing dead cells to maintain health. It is increasingly appreciated that this process requires rapid degradation the corpse metabolic load to maintain normal macrophage functions and mount appropriate immune responses. To understand conserved reprogramming associated with successful corpse engulfment, this study compares RNA-sequencing on three different macrophage populations in mice to understand conserved programming downstream of apoptotic cell engulfment in vitro and in vivo. Pathway analysis identifies enrichment of conserved pathways related to metabolite handling in all three engulfing macrophage populations, including pathways related to metal ion homeostasis. Our study identifies metals as part of the corpse-derived metabolic load transferred to macrophages. We demonstrate a conserved role of macrophage metallothionein (MT) gene upregulation in the management of cell-derived metals transferred during engulfment of apoptotic corpses, necrotic corpses, or live cells. Mechanistically, MTs facilitate prompt control of free zinc released during corpse degradation in the phagolysosome. MTs are necessary for macrophages to enhance oxidative phosphorylation in response to apoptotic cell engulfment, connecting control of corpse-derived metals to macrophage metabolic response. Collectively, these findings identify metals as micronutrients transferred from corpses to engulfing macrophages during efferocytosis and other corpse clearance and demonstrate an important role for metallothioneins in processing corpse-associated metals to preserve macrophage functions.