2026-09-23T10:56:16Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/277042026-09-12T00:17:18Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605

00925njm 22002777a 4500 dc Priego, Elena author Adan-Barrientos, Irene author Conde-Garrosa, Ruth author Martínez-Cano, Sarai author Sánchez, Iria author Mañanes, Diego author Mastrangelo, Annalaura author Amores-Iniesta, Joaquín author Izquierdo, Helena M author Sancho, David author 2026-06-23 Alveolar macrophages (AMs) reside in the oxygen-rich alveoli, where hypoxia-inducible transcription factor (HIF) subunits are targeted for degradation by the Von Hippel-Lindau protein (pVHL). We previously showed that Vhl-deficient AMs are immature and functionally impaired. Here, we define isoform-specific roles of HIF-1α and HIF-2α in the regulation of AM maturation and function. Expression of either isoform alone is sufficient to intrinsically, and differentially, impair AM terminal maturation and self-renewal, with complete rescue observed only when both HIF-1α and HIF-2α are deleted in Vhl-deficient AMs. HIF-1α drives glycolytic reprogramming in AMs, while HIF-2α disrupts fatty acid oxidation and surfactant clearance. Consequently, HIF-2α stabilization limits the capacity of AMs to resolve surfactant excess in a mouse model of pulmonary alveolar proteinosis, indicating HIF-2α as a potential therapeutic target. Overall, HIF inactivation ensures optimal AM maturation and metabolic adaptation to the high-oxygen alveolar niche, revealing non-redundant functional specificities of each HIF-α isoform. Cell Rep. 2026 Jun 23;45(6):117447. CELL REPORTS 42207632 https://hdl.handle.net/20.500.12105/27704 Alveolar Macrophage CP: Immunology CP: Metabolism HIF glycolysis mitochondrial respiration self-renewal surfactant oxidation HIF-1α and HIF-2α differentially regulate alveolar macrophage maturation and function.