Max-Delbrück-Center for Molecular Medicine in Helmholtz Association (MDC), Berlin, Germany.
Institute of Biology, Humboldt University of Berlin, Berlin, Germany.
Sci Immunol. 2022 Sep 16;7(75):eabj0140. doi: 10.1126/sciimmunol.abj0140.
Pulmonary alveolar proteinosis (PAP) is a syndrome characterized by accumulation of surfactant lipoproteins within the lung alveoli. Alveolar macrophages (AMs) are crucial for surfactant clearance, and their differentiation depends on colony-stimulating factor 2 (CSF2), which regulates the establishment of an AM-characteristic gene regulatory network. Here, we report that the transcription factor CCAAT/enhancer binding protein β (C/EBPβ) is essential for the development of the AM identity, as demonstrated by transcriptome and chromatin accessibility analysis. Furthermore, C/EBPβ-deficient AMs showed severe defects in proliferation, phagocytosis, and lipid metabolism, collectively resulting in a PAP-like syndrome. Mechanistically, the long C/EBPβ protein variants LAP* and LAP together with CSF2 signaling induced the expression of isoform 2 but not isoform 1, a molecular regulatory mechanism that was also observed in other CSF2-primed macrophages. These results uncover C/EBPβ as a key regulator of AM cell fate and shed light on the molecular networks controlling lipid metabolism in macrophages.
肺泡蛋白沉积症（PAP）是一种以肺肺泡内表面活性剂脂蛋白蓄积为特征的综合征。肺泡巨噬细胞（AMs）对于表面活性剂的清除至关重要，其分化依赖于集落刺激因子 2（CSF2），后者调节 AM 特征性基因调控网络的建立。在这里，我们报告转录因子 CCAAT/增强子结合蛋白 β（C/EBPβ）对于 AM 特性的发展是必不可少的，这可以通过转录组和染色质可及性分析来证明。此外，C/EBPβ缺陷型 AMs 在增殖、吞噬和脂质代谢方面表现出严重缺陷，共同导致 PAP 样综合征。从机制上讲，长型 C/EBPβ蛋白变体 LAP*和 LAP 与 CSF2 信号共同诱导 异构体 2 的表达，但不诱导 异构体 1 的表达，这是一种在其他 CSF2 激活的巨噬细胞中也观察到的分子调控机制。这些结果揭示了 C/EBPβ 是 AM 细胞命运的关键调节剂，并阐明了控制巨噬细胞脂质代谢的分子网络。
