Microglia are the resident macrophages of the central nervous system (CNS). Their phagocytic activity is central during brain development and homeostasis—and in a plethora of brain pathologies. However, little is known about the composition, dynamics, and function of human microglial phagosomes under homeostatic and pathological conditions. Here, we developed a method for rapid isolation of pure and intact phagosomes from human pluripotent stem cell-derived microglia under various in vitro conditions, and from human brain biopsies, for unbiased multiomic analysis. Phagosome profiling revealed that microglial phagosomes were equipped to sense minute changes in their environment and were highly dynamic. We detected proteins involved in synapse homeostasis, or implicated in brain pathologies, and identified the phagosome as the site where quinolinic acid was stored and metabolized for de novo nicotinamide adenine dinucleotide (NAD⁺) generation in the cytoplasm. Our findings highlight the central role of phagosomes in microglial functioning in the healthy and diseased brain.

小胶质细胞是中枢神经系统（CNS）的常驻巨噬细胞。它们的吞噬细胞活动在大脑发育和体内平衡以及大量的大脑病理过程中发挥着核心作用。然而，人们对人小胶质细胞吞噬体在稳态和病理条件下的组成、动力学和功能知之甚少。在这里，我们开发了一种在各种体外条件下从人多能干细胞衍生的小胶质细胞以及人脑活检中快速分离纯且完整的吞噬体的方法，以进行无偏见的多组学分析。吞噬体分析表明，小胶质细胞吞噬体能够感知环境中的微小变化，并且具有高度动态性。我们检测到涉及突触稳态或与脑病理学有关的蛋白质，并确定吞噬体是喹啉酸在细胞质中储存和代谢以从头产生烟酰胺腺嘌呤二核苷酸（NAD ⁺ ）的位点。我们的研究结果强调了吞噬体在健康和患病大脑的小胶质细胞功能中的核心作用。