HIF-1α and HIF-2α differentially regulate alveolar macrophage maturation and function

Area of Science:

• Pulmonary immunology
• Cellular metabolism
• Molecular biology

Background:

• Alveolar macrophages (AMs) are crucial immune cells in the lung's high-oxygen environment.
• The Von Hippel-Lindau protein (pVHL) targets hypoxia-inducible transcription factor (HIF) subunits for degradation.
• Previous work indicated Vhl-deficient AMs exhibit immature phenotypes and impaired function.

Purpose of the Study:

• To define the specific roles of HIF-1α and HIF-2α isoforms in regulating AM maturation and function.
• To investigate the metabolic reprogramming driven by HIF isoforms in AMs.
• To assess the therapeutic potential of targeting HIF-2α in lung disease models.

Main Methods:

• Genetic manipulation of Vhl and HIF isoforms in mouse AMs.
• Analysis of AM maturation, self-renewal, and metabolic pathways (glycolysis, fatty acid oxidation).
• Utilizing a mouse model of pulmonary alveolar proteinosis to evaluate AM function in vivo.

Main Results:

• Expression of either HIF-1α or HIF-2α alone in Vhl-deficient AMs impairs terminal maturation and self-renewal.
• Complete rescue of AM maturation and function requires deletion of both HIF-1α and HIF-2α.
• HIF-1α promotes glycolytic reprogramming, while HIF-2α disrupts fatty acid oxidation and surfactant clearance.
• Stabilized HIF-2α limits AMs' ability to resolve surfactant excess in a pulmonary alveolar proteinosis model.

Conclusions:

• HIF inactivation is essential for optimal AM maturation and metabolic adaptation to the alveolar niche.
• HIF-1α and HIF-2α possess non-redundant, isoform-specific functions in AM regulation.
• HIF-2α represents a potential therapeutic target for conditions involving impaired surfactant clearance, such as pulmonary alveolar proteinosis.