Myelopoiesis is necessary for the generation of mature myeloid cells during homeostatic turnover and immunological insults; however, the metabolic requirements for this process remain poorly defined. Here, we demonstrate that myelopoiesis, including monocyte and macrophage differentiation, requires mechanistic target of rapamycin complex 1 (mTORC1) signaling and anabolic metabolism. Loss of mTORC1 impaired myelopoiesis under steady state and dampened innate immune responses against Listeria monocytogenes infection. Stimulation of hematopoietic progenitors with macrophage colony-stimulating factor (M-CSF) resulted in mTORC1-dependent anabolic metabolism, which in turn promoted expression of M-CSF receptor and transcription factors PU.1 and IRF8, thereby constituting a feed-forward loop for myelopoiesis. Mechanistically, mTORC1 engaged glucose metabolism and initiated a transcriptional program involving Myc activation and sterol biosynthesis after M-CSF stimulation. Perturbation of glucose metabolism or disruption of Myc function or sterol biosynthesis impaired myeloid differentiation. Integrative metabolomic and genomic profiling further identified one-carbon metabolism as a central node in mTORC1-dependent myelopoiesis. Therefore, the interplay between mTORC1 signaling and metabolic reprogramming underlies M-CSF–induced myelopoiesis.

在稳态转换和免疫损伤期间，骨髓生成对于生成成熟的髓样细胞是必需的。然而，该过程的代谢要求仍然定义不清。在这里，我们证明，包括单核细胞和巨噬细胞分化在内的骨髓生成需要雷帕霉素复合物1（mTORC1）信号转导和合成代谢的机制目标。稳定状态下mTORC1的缺失会破坏骨髓细胞生成，并减弱针对单核细胞增生性李斯特菌的先天免疫反应感染。巨噬细胞集落刺激因子（M-CSF）刺激造血祖细胞导致mTORC1依赖的合成代谢代谢，进而促进M-CSF受体和转录因子PU.1和IRF8的表达，从而构成前馈环骨髓生成。机械上，mTORC1参与葡萄糖代谢，并在M-CSF刺激后启动了涉及Myc激活和固醇生物合成的转录程序。葡萄糖代谢紊乱或Myc功能破坏或固醇生物合成削弱了髓样分化。整合的代谢组学和基因组图谱进一步确定了一碳代谢是mTORC1依赖性骨髓生成的中心节点。因此，mTORC1信号和代谢重编程之间的相互作用是M-CSF诱导的骨髓生成的基础。