Tissue macrophages are immune cells whose phenotypes and functions are dictated by origin and niches. However, tissues are complex environments, and macrophage heterogeneity within the same organ has been overlooked so far. Here, we used high-dimensional approaches to characterize macrophage populations in the murine liver. We identified two distinct populations among embryonically derived Kupffer cells (KCs) sharing a core signature while differentially expressing numerous genes and proteins: a major CD206^loESAM^– population (KC1) and a minor CD206^hiESAM⁺ population (KC2). KC2 expressed genes involved in metabolic processes, including fatty acid metabolism both in steady-state and in diet-induced obesity and hepatic steatosis. Functional characterization by depletion of KC2 or targeted silencing of the fatty acid transporter Cd36 highlighted a crucial contribution of KC2 in the liver oxidative stress associated with obesity. In summary, our study reveals that KCs are more heterogeneous than anticipated, notably describing a subpopulation wired with metabolic functions.

组织巨噬细胞是免疫细胞，其表型和功能由起源和生态位决定。然而，组织是复杂的环境，迄今为止，同一器官内的巨噬细胞异质性一直被忽视。在这里，我们使用高维方法来表征小鼠肝脏中的巨噬细胞群。我们在胚胎衍生的库普弗细胞 (KCs) 中鉴定出两个不同的群体，它们共享一个核心特征，同时差异性地表达许多基因和蛋白质：主要的 CD206 ^lo ESAM ^–群体 (KC1) 和次要的 CD206 ^hi ESAM ⁺人口（KC2）。KC2 表达参与代谢过程的基因，包括稳态和饮食诱导的肥胖和肝脂肪变性中的脂肪酸代谢。KC2 的消耗或脂肪酸转运蛋白Cd36 的靶向沉默的功能表征突出了 KC2 在与肥胖相关的肝脏氧化应激中的关键贡献。总之，我们的研究表明 KCs 比预期的更加异质，特别是描述了一个具有代谢功能的亚群。