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

Pathog Dis. 2020 Jul 1;78(5):ftaa038. doi: 10.1093/femspd/ftaa038.

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.

Keywords: Aspergillus fumigatus; hyperglycemia; hypoxia-inducible factor-1α.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids, Dicarboxylic / pharmacology*
  • Animals
  • Aspergillus fumigatus / drug effects*
  • Aspergillus fumigatus / pathogenicity
  • Cell Differentiation / drug effects
  • Diabetes Mellitus, Experimental / chemically induced
  • Diabetes Mellitus, Experimental / complications
  • Disease Models, Animal
  • Gene Expression Regulation / drug effects
  • Host-Pathogen Interactions
  • Hyperglycemia / metabolism
  • Hyperglycemia / microbiology*
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Interleukin-1beta / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
  • Pulmonary Aspergillosis / complications
  • Pulmonary Aspergillosis / microbiology*
  • Signal Transduction
  • T-Lymphocytes, Helper-Inducer / drug effects
  • T-Lymphocytes, Regulatory / drug effects

Substances

  • Amino Acids, Dicarboxylic
  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • IL1B protein, mouse
  • Interleukin-1beta
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • oxalylglycine