Macrophage differentiation requires DNA damage caused by Caspase-Activated DNase

Phagocytic macrophages are crucial for innate immunity and tissue homeostasis. Most macrophages develop from embryonic precursors that populate every organ before birth to self-renew lifelong. However, the mechanisms for macrophage differentiation remain unknown. Using in vivo genetic analysis of the Drosophila larval hematopoietic organ, the lymph gland, we show that the developmentally regulated transient activation of Caspase-Activated DNase (CAD)-mediated DNA breaks in intermediate progenitors is essential for macrophage differentiation. Insulin receptor-mediated PI3K/Akt signaling triggers apoptotic signaling and causes DNA breaks during macrophage development. However, the same Akt signaling attenuates Apoptosis signal-regulating kinase 1 (Ask1) to control apoptotic and JNK activity in differentiating macrophages. DNA-damaged differentiating cells display autophagy activity as a survival strategy. Furthermore, caspase activity is required for embryonic-origin macrophage development and efficient phagocytosis. This study reveals a previously unknown relationship between developmental signals and caspase-activated DNA breaks necessary for multifunctional macrophage differentiation.