Myeloid Derived Hypoxia Inducible Factor 1-alpha Is Required for Protection against Pulmonary Aspergillus fumigatus Infection

Abstract

Hypoxia inducible factor 1α (HIF1α) is the mammalian transcriptional factor that controls metabolism, survival, and innate immunity in response to inflammation and low oxygen. Previous work established that generation of hypoxic microenvironments occurs within the lung during infection with the human fungal pathogen Aspergillus fumigatus. Here we demonstrate that A. fumigatus stabilizes HIF1α protein early after pulmonary challenge that is inhibited by treatment of mice with the steroid triamcinolone. Utilizing myeloid deficient HIF1α mice, we observed that HIF1α is required for survival and fungal clearance early following pulmonary challenge with A. fumigatus. Unlike previously reported research with bacterial pathogens, HIF1α deficient neutrophils and macrophages were surprisingly not defective in fungal conidial killing. The increase in susceptibility of the myeloid deficient HIF1α mice to A. fumigatus was in part due to decreased early production of the chemokine CXCL1 (KC) and increased neutrophil apoptosis at the site of infection, resulting in decreased neutrophil numbers in the lung. Addition of recombinant CXCL1 restored neutrophil survival and numbers, murine survival, and fungal clearance. These results suggest that there are unique HIF1α mediated mechanisms employed by the host for protection and defense against fungal pathogen growth and invasion in the lung. Additionally, this work supports the strategy of exploring HIF1α as a therapeutic target in specific immunosuppressed populations with fungal infections.

Endothelial Hypoxia-Inducible Factor-1α Promotes Atherosclerosis and Monocyte Recruitment by Upregulating MicroRNA-19a

“…HIF-1α transcriptional activity is also required for CXCL1 expression in myeloid cells, which mediates the survival of neutrophils in mycosis. 9 In ECs, preformed CXCL1 is stored in vesicles and released on activation by LPA. 6 CXCL1 is immobilized on the endothelial surface and induces proatherogenic monocyte adhesion by binding to its receptor CXCR2.…”

Hypoxia-inducible factors: key regulators of myeloid cells during inflammation

“…Shepardson and colleagues found that mice with myeloid HIF-1α deficiency are more susceptible to pulmonary challenge with Aspergillus fumigatus, are defective in fungal clearance, and exhibit decreased lung neutrophil numbers. These phenotypes can be partly attributed to decreased production of CXCL1 and increased neutrophil apoptosis (148). Contradictory to the finding that macrophage HIF-1α prevents airway allergy, a study by Byrne and colleagues suggests that development of airway allergy is dependent on macrophage HIF-1α.…”

Innate Lung Defense during Invasive Aspergillosis: New Mechanisms

“…Hypoxia-inducible factor 1 (HIF-1)α is a host transcription factor that mediates multiple functions during periods of low oxygen. A. fumigatus has recently been shown to stabilize HIF-1α in the lung, a process interrupted by CT [66] . Mice with HIF-1α deletion in myeloid cells rapidly succumb to IA as a result of impaired neutrophil recruitment to the lungs and enhanced neutrophil apoptosis [66] .…”

“…A. fumigatus has recently been shown to stabilize HIF-1α in the lung, a process interrupted by CT [66] . Mice with HIF-1α deletion in myeloid cells rapidly succumb to IA as a result of impaired neutrophil recruitment to the lungs and enhanced neutrophil apoptosis [66] . A recent study documented that mice deficient in CXCR2 and those immunosuppressed with corticosteroids display defective clearance of A. fumigatus from the lungs in the presence of increased hypoxia and increased levels of proinflammatory cytokines, including IL-1α and IL-1β [67] .…”