Peroxisomes are critical for a unique metabolic demand and survival of alveolar macrophages

Tissue-resident macrophages (TRMs) populate throughout various tissues, and their homeostatic metabolism is heavily influenced by these microenvironments. Peroxisomes are organelles that contribute to lipid metabolism. However, the involvement of these organelles in the bioenergetics of TRMs remains undetermined. We conducted a developmental screen of TRMs using a conditional peroxisomal biogenesis factor 5 (Pex5) knockout mouse model that lacks functional peroxisomes in all immune cell subsets. Pulmonary alveolar macrophages (AMs) appeared as the only subset of TRMs that required functional peroxisomes for their development. Pex5-deficiency resulted in reduced AM survival due to increased sensitivity to lipotoxicity, in line with excess accumulation of ceramides. The absence of peroxisomes had a significant effect on overall mitochondrial fitness and altered their metabolic program, allowing them to engage in glycolysis in addition to oxidative phosphorylation. Our results revealed that AMs have a unique metabolic regulation, where peroxisomes play a central role for their homeostatic development and maintenance. Bulk RNA Sequencing of BAL AMs isolated from Pex5fl/fl and Vav1cre/+ and Pex5fl/fl mice组织驻留巨噬细胞（Tissue-resident macrophages, TRMs）广泛分布于全身各组织，其稳态代谢显著受所处微环境的调控。过氧化物酶体（Peroxisomes）是参与脂质代谢的细胞器。然而，此类细胞器是否参与组织驻留巨噬细胞的能量代谢过程仍有待阐明。本研究借助一种条件性过氧化物酶体生物发生因子5（Pex5）敲除小鼠模型——该模型所有免疫细胞亚群均缺失功能性过氧化物酶体——对组织驻留巨噬细胞开展了发育筛选实验。结果显示，肺泡巨噬细胞（Pulmonary alveolar macrophages, AMs）是唯一依赖功能性过氧化物酶体完成正常发育的组织驻留巨噬细胞亚群。Pex5基因缺陷会使肺泡巨噬细胞对脂毒性的敏感性升高，进而导致其存活能力下降，这一现象与神经酰胺的过度积累相一致。过氧化物酶体的缺失会显著影响线粒体整体健康状态，并重塑肺泡巨噬细胞的代谢程序，使其除可进行氧化磷酸化外，还可激活糖酵解途径。本研究结果揭示，肺泡巨噬细胞存在独特的代谢调控机制，而过氧化物酶体在其稳态发育与功能维持过程中发挥核心作用。本研究对分离自Pex5fl/fl小鼠以及Vav1cre/+与Pex5fl/fl小鼠的支气管肺泡灌洗肺泡巨噬细胞开展了批量RNA测序（Bulk RNA Sequencing）。