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

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).