Apocynin and Nox2 Regulate NF-κB by Modifying thioredoxin-1 Redox-State

Sci Rep. 2016 Oct 4;6:34581. doi: 10.1038/srep34581.

Abstract

The reactive-oxygen-species-(ROS)-generating-enzyme Nox2 is essential for leukocyte anti-microbial activity. However its role in cellular redox homeostasis and, consequently, in modulating intracellular signaling pathways remains unclear. Herein, we show Nox2 activation favors thioredoxin-1 (TRX-1)/p40phox interaction, which leads to exclusion of TRX-1 from the nucleus. In contrast, the genetic deficiency of Nox2 or its pharmacological inhibition with apocynin (APO) results in reductive stress after lipopolysaccharide-(LPS)-cell stimulation, which causes nuclear accumulation of TRX-1 and enhanced transcription of inflammatory mediators through nuclear-factor-(NF)-κB. The NF-κB overactivation is prevented by TRX-1 oxidation using inhibitors of thioredoxin reductase-1 (TrxR-1). The Nox2/TRX-1/NF-κB intracellular signaling pathway is involved in the pathophysiology of chronic granulomatous disease (CGD) and sepsis. In fact, TrxR-1 inhibition prevents nuclear accumulation of TRX-1 and LPS-stimulated hyperproduction of tumor-necrosis-factor-(TNF)-α by monocytes and neutrophils purified from blood of CGD patients, who have deficient Nox2 activity. TrxR-1 inhibitors, either lanthanum chloride (LaCl3) or auranofin (AUR), also increase survival rates of mice undergoing cecal-ligation-and-puncture-(CLP). Therefore, our results identify a hitherto unrecognized Nox2-mediated intracellular signaling pathway that contributes to hyperinflammation in CGD and in septic patients. Additionally, we suggest that TrxR-1 inhibitors could be potential drugs to treat patients with sepsis, particularly in those with CGD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetophenones / pharmacology*
  • Animals
  • Granulomatous Disease, Chronic / chemically induced
  • Granulomatous Disease, Chronic / genetics
  • Granulomatous Disease, Chronic / metabolism
  • Granulomatous Disease, Chronic / pathology
  • Lipopolysaccharides / toxicity
  • Male
  • Mice
  • Mice, Knockout
  • NADPH Oxidase 2 / genetics
  • NADPH Oxidase 2 / metabolism*
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Oxidation-Reduction / drug effects
  • Sepsis / chemically induced
  • Sepsis / genetics
  • Sepsis / metabolism
  • Sepsis / pathology
  • Signal Transduction / drug effects*
  • Thioredoxins / genetics
  • Thioredoxins / metabolism*

Substances

  • Acetophenones
  • Lipopolysaccharides
  • NF-kappa B
  • Txn1 protein, mouse
  • Thioredoxins
  • acetovanillone
  • Cybb protein, mouse
  • NADPH Oxidase 2