Cytogenetics Laboratory, Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi 221005, India.
Cytogenetics Laboratory, Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi 221005, India.
Cell Rep. 2024 May 28;43(5):114251. doi: 10.1016/j.celrep.2024.114251. Epub 2024 May 17.
Phagocytic macrophages are crucial for innate immunity and tissue homeostasis. Most tissue-resident macrophages develop from embryonic precursors that populate every organ before birth to lifelong self-renew. However, the mechanisms for versatile macrophage differentiation remain unknown. Here, we use in vivo genetic and cell biological analysis of the Drosophila larval hematopoietic organ, the lymph gland that produces macrophages. We show that the developmentally regulated transient activation of caspase-activated DNase (CAD)-mediated DNA strand breaks in intermediate progenitors is essential for macrophage differentiation. Insulin receptor-mediated PI3K/Akt signaling regulates the apoptosis signal-regulating kinase 1 (Ask1)/c-Jun kinase (JNK) axis to control sublethal levels of caspase activation, causing DNA strand breaks during macrophage development. Furthermore, caspase activity is also required for embryonic-origin macrophage development and efficient phagocytosis. Our study provides insights into developmental signaling and CAD-mediated DNA strand breaks associated with multifunctional and heterogeneous macrophage differentiation.
吞噬性巨噬细胞对于先天免疫和组织稳态至关重要。大多数组织驻留巨噬细胞来源于胚胎前体，这些前体在出生前遍布每个器官，以实现终身自我更新。然而，多功能巨噬细胞分化的机制尚不清楚。在这里，我们使用活体遗传和细胞生物学分析果蝇幼虫造血器官——产生巨噬细胞的血腔，来证明中间祖细胞中 Caspase 激活的 DNA 内切酶（CAD）介导的 DNA 链断裂的发育调控性短暂激活对于巨噬细胞分化是必不可少的。胰岛素受体介导的 PI3K/Akt 信号转导调节凋亡信号调节激酶 1（Ask1）/c-Jun 激酶（JNK）轴以控制 caspase 激活的亚致死水平，导致巨噬细胞发育过程中的 DNA 链断裂。此外，caspase 活性对于胚胎起源的巨噬细胞发育和有效的吞噬作用也是必需的。我们的研究为多功能和异质巨噬细胞分化相关的发育信号和 CAD 介导的 DNA 链断裂提供了新的见解。
