Hyperglycemia suppresses the regulatory effect of hypoxia-inducible factor-1α in pulmonary Aspergillus fumigatus infection

ABSTRACT Aspergillus fumigatus is one of the most common fungal infections involved in the pulmonary diseases. Hypoxia-inducible factor-1α (HIF-1α) is important for antifungal immunity. Diabetes is a risk factor of pulmonary A. fumigatus infection and could affect the expression of HIF-1α. The aim of this investigation was to evaluate the role of HIF-1α in pulmonary A. fumigatus infection in diabetes. In murine model, we found diabetic mice had aggravated pulmonary A. fumigatus infection and declined expression of HIF-1α following pulmonary A. fumigatus infection. And these changes could be corrected by dimethyloxalylglycine (DMOG), the agonist of HIF-1α. In cell experiment, after A. fumigatus stimulation, hyperglycemic state was with a decreased HIF-1α expression and increased NLRP3/IL-1β signal pathway. The percentages of Th1 and Treg cells decreased, while percentages of Th2 and Th17 increased in hyperglycemic group. DMOG suppressed A. fumigatus-stimulated NLRP3 and IL-1β expressions in hyperglycemic group and corrected Th and Treg cells differentiation. These regulatory effects of DMOG could be dampened by activating of NLRP3. These data indicated that hyperglycemia suppressed the regulatory effect of HIF-1α in pulmonary A. fumigatus infection, which can affect Th and Treg cells differentiation by regulating the NLRP3/IL-1β signal pathway. With animal model and cell experiments, a so far unraveled mechanism for the hypoxia-inducible factor-1α in pulmonary Aspergillus fumigatus infection in diabetes was explored.