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HIF-1α and HIF-2α transcription factors differentially regulate lung alveolar macrophage function

ABSTRACT: Alveolar Macrophages (AMs) reside in the alveoli, therefore maintaining an active degradation of hypoxia-inducible transcription factors (HIF) mediated by Von Hippel-Lindau protein (pVHL). We previously found that Vhl-deficient AMs are immature and functionally impaired. Here we investigated the specific contribution of HIF-1α and HIF-2α isoforms to the regulation of the AM function. Our work demonstrates that in Vhl-deficient macrophages, both HIF-1α and HIF-2α contribute to AM defective self-renewal, while HIF-2α plays a central role in regulating the impaired AM maturation associated with pVHL loss. HIF-1α promotes a glycolytic shift in alveolar macrophages, while HIF-2α hinders lipid oxidation and surfactant clearance. Thus, HIF-2α raises as a selective critical factor restraining the therapeutic potential of AMs to degrade surfactant excess in mice that have developed pulmonary alveolar proteinosis (PAP). Overall, regulation of both HIF-1α and HIF-2α isoforms is required for an optimal AM function.

ORGANISM(S): Mus musculus

PROVIDER: GSE325293 | GEO | 2026/03/23

REPOSITORIES: GEO

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Project description:To investigate the detailed molecular mechanisms for the regulatory role of HIF-2α in experimental colitis, microarray gene expression analysis was performed on colon RNA isolated from 6- to 8-week-old Hif-2αF/F, Hif-2αlΔIE mice treated with 3%DSS for 3 days. Background & Aims: Hypoxic inflammation is characterized by decreased oxygen tension in inflammatory foci, and is a notable feature in inflammatory bowel disease (IBD). Hypoxic response is mediated by transcription factors hypoxia-inducible factor (HIF)-1α and HIF-2α, both of which are highly induced in IBD. HIF-1α is a protective factor that limits intestinal barrier dysfunction during inflammation. However, the role of HIF-2α has not been assessed in hypoxic inflammation and IBD. Methods: A hypoxia reporter mouse model was used to test the presence of hypoxia and HIF-2α in dextran sulfate sodium (DSS) and Citrobacter rodentium (C.rod)-induced colitis. The role of HIF-2α in these mouse models of colitis was further assessed in mice with an intestinal epithelium-specific gain- and loss-of-function of HIF-2α. Results: Induction of hypoxia and HIF-2α was confirmed in both murine experimental colitis models and human IBD samples. Disruption of HIF-2α attenuated colonic inflammation whereas stabilization of HIF-2α potentiated inflammation in mouse models of colitis. Interestingly, intestine specific overexpression of HIF-2α but not HIF-1α leads to spontaneous colitis and premature death in mice. Further mechanistic analysis showed that HIF-2α is a driver for pro-inflammatory response and is critical regulator of intestinal epithelial-derived tumor necrosis factor (TNF)-α. Blocking TNF-α completely ameliorated HIF-2α potentiated intestinal inflammation. Conclusions: These data demonstrate that HIF-2α is a critical transcription factor essential in intestinal epithelium elicited inflammatory response. Global gene expression profiling in colon RNAs isolated from 7-week-old Hif-2αF/F (n=6, Shah 007) and Hif-2αΔIE (n=5, Shah 008).

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HIF-1α and HIF-2α transcription factors differentially regulate lung alveolar macrophage function

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