Woods Parker S, Cetin-Atalay Rengül, Meliton Angelo Y, Sun Kaitlyn A, Shamaa Obada R, Shin Kun Woo D, Tian Yufeng, Haugen Benjamin, Hamanaka Robert B, Mutlu Gökhan M
Department of Medicine, Section of Pulmonary and Critical Care Medicine, The University of Chicago, 5841 S. Maryland Avenue MC6026, Chicago, IL, 60637, USA.
Sci Rep. 2025 Apr 4;15(1):11574. doi: 10.1038/s41598-025-95962-3.
HIF-1α plays a critical role in shaping macrophage phenotype and effector function. We have previously shown that tissue-resident alveolar macrophages (TR-AMs) have extremely low glycolytic capacity at steady-state but can shift toward glycolysis under hypoxic conditions. Here, we generated mice with tamoxifen-inducible myeloid lineage cell specific deletion of Hif1a (Hif1a:LysM-CreERT2) and from these mice, we isolated TR-AMs and bone marrow-derived macrophages (BMDMs) in which Hif1a is deleted. We show that TR-AM HIF-1α is required for the glycolytic shift under prolyl hydroxylase inhibition but is dispensable at steady-state for inflammatory effector function. In contrast, HIF-1α deletion in BMDMs led to diminished glycolytic capacity at steady-state and reduced inflammatory capacity, but higher mitochondrial function. Gene set enrichment analysis revealed enhanced c-Myc transcriptional activity in Hif1a BMDMs, and upregulation of gene pathways related to ribosomal biogenesis and cellular proliferation. We conclude that HIF-1α regulates mitochondrial function in BMDMs but not in TR-AMs. The findings highlight the heterogeneity of HIF-1α function in distinct macrophage populations and provide new insight into how HIF-1α regulates gene expression, inflammation, and metabolism in different types of macrophages.
缺氧诱导因子-1α（HIF-1α）在塑造巨噬细胞表型和效应功能方面发挥着关键作用。我们之前已经表明，组织驻留肺泡巨噬细胞（TR-AMs）在稳态下糖酵解能力极低，但在缺氧条件下可转向糖酵解。在此，我们构建了他莫昔芬诱导的髓系谱系细胞特异性缺失Hif1a的小鼠（Hif1a:LysM-CreERT2），并从这些小鼠中分离出Hif1a被缺失的TR-AMs和骨髓来源的巨噬细胞（BMDMs）。我们发现，脯氨酰羟化酶抑制下的糖酵解转变需要TR-AM HIF-1α，但在稳态下对炎症效应功能而言并非必需。相反，BMDMs中HIF-1α的缺失导致稳态下糖酵解能力减弱和炎症能力降低，但线粒体功能增强。基因集富集分析显示，Hif1a BMDMs中c-Myc转录活性增强，与核糖体生物发生和细胞增殖相关的基因通路上调。我们得出结论，HIF-1α调节BMDMs中的线粒体功能，但不调节TR-AMs中的线粒体功能。这些发现突出了HIF-1α在不同巨噬细胞群体中功能的异质性，并为HIF-1α如何调节不同类型巨噬细胞中的基因表达、炎症和代谢提供了新的见解。
