Impaired inflammasome activation and bacterial clearance in G6PD deficiency due to defective NOX/p38 MAPK/AP-1 redox signaling

Redox Biol. 2020 Jan:28:101363. doi: 10.1016/j.redox.2019.101363. Epub 2019 Nov 2.

Abstract

Glucose-6-phosphate dehydrogenase (G6PD) is the rate-limiting enzyme of the pentose phosphate pathway that modulates cellular redox homeostasis via the regeneration of NADPH. G6PD-deficient cells have a reduced ability to induce the innate immune response, thus increasing host susceptibility to pathogen infections. An important part of the immune response is the activation of the inflammasome. G6PD-deficient peripheral blood mononuclear cells (PBMCs) from patients and human monocytic (THP-1) cells were used as models to investigate whether G6PD modulates inflammasome activation. A decreased expression of IL-1β was observed in both G6PD-deficient PBMCs and PMA-primed G6PD-knockdown (G6PD-kd) THP-1 cells upon lipopolysaccharide (LPS)/adenosine triphosphate (ATP) or LPS/nigericin stimulation. The pro-IL-1β expression of THP-1 cells was decreased by G6PD knockdown at the transcriptional and translational levels in an investigation of the expression of the inflammasome subunits. The phosphorylation of p38 MAPK and downstream c-Fos expression were decreased upon G6PD knockdown, accompanied by decreased AP-1 translocation into the nucleus. Impaired inflammasome activation in G6PD-kd THP-1 cells was mediated by a decrease in the production of reactive oxygen species (ROS) by NOX signaling, while treatment with hydrogen peroxide (H2O2) enhanced inflammasome activation in G6PD-kd THP-1 cells. G6PD knockdown decreased Staphylococcus aureus and Escherichia coli clearance in G6PD-kd THP-1 cells and G6PD-deficient PBMCs following inflammasome activation. These findings support the notion that enhanced pathogen susceptibility in G6PD deficiency is, in part, due to an altered redox signaling, which adversely affects inflammasome activation and the bactericidal response.

Keywords: Bactericidal response; G6PD; IL-1β; Inflammasome; NADPH oxidase; Redox homeostasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Case-Control Studies
  • Down-Regulation
  • Female
  • Gene Knockdown Techniques
  • Glucosephosphate Dehydrogenase Deficiency / genetics
  • Glucosephosphate Dehydrogenase Deficiency / immunology*
  • Glucosephosphate Dehydrogenase Deficiency / microbiology
  • HEK293 Cells
  • Humans
  • Interleukin-1beta / genetics*
  • Interleukin-1beta / metabolism*
  • Leukocytes, Mononuclear / cytology
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / immunology
  • Lipopolysaccharides / adverse effects
  • Male
  • NADPH Oxidases / metabolism*
  • THP-1 Cells / drug effects
  • THP-1 Cells / immunology
  • THP-1 Cells / microbiology
  • Transcription Factor AP-1 / metabolism*
  • Young Adult
  • p38 Mitogen-Activated Protein Kinases / metabolism*

Substances

  • IL1B protein, human
  • Interleukin-1beta
  • Lipopolysaccharides
  • Transcription Factor AP-1
  • NADPH Oxidases
  • p38 Mitogen-Activated Protein Kinases