Hypoxia potentiates LPS-induced inflammatory response and increases cell death by promoting NLRP3 inflammasome activation in pancreatic β cells

Biochem Biophys Res Commun. 2018 Jan 22;495(4):2512-2518. doi: 10.1016/j.bbrc.2017.12.134. Epub 2017 Dec 24.

Abstract

Hypoxia and islet inflammation are involved in β-cell failure in type 2 diabetes (T2D). Elevated plasma LPS levels have been verified in patients with T2D, and hypoxia occurs in islets of diabetic mice. Activation of inflammasomes in ischemic or hypoxic conditions was identified in various tissues. Here, we investigated whether hypoxia activates the inflammasome in β cells and the possible mechanisms involved. In mouse insulinoma cell line 6 (MIN6), hypoxia (1% O2) primes the NLRP3 inflammasome along with NF-κB signaling activation. Our results demonstrate that hypoxia can activate the NLRP3 inflammasome in LPS-primed MIN6 to result in initiating the β cell inflammatory response and cell death in vitro. Reactive oxygen species (ROS) and the thioredoxin-interacting protein (TXNIP) are up-regulated in response to hypoxia. Finally, the role of the ROS-TXNIP axis in mediating the activation of the NLRP3 inflammasome and cell death was characterized by pretreating with the ROS scavenger N-acetylcysteine (NAC) and performing TXNIP knockdown experiments in MIN6. Our data indicate for the first time that the inflammasome is involved in the inflammatory response and cell death in hypoxia-induced β cells through the ROS-TXNIP-NLRP3 axis in vitro. This provides new insight into the relationship between hypoxia and inflammation in T2D.

Keywords: Diabetes; Hypoxia; Inflammasome; Islet inflammation; TXNIP; β cell.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / immunology*
  • Carrier Proteins / immunology*
  • Cell Hypoxia / drug effects
  • Cell Hypoxia / immunology*
  • Cell Line
  • Inflammasomes / drug effects
  • Inflammasomes / immunology*
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / immunology*
  • Lipopolysaccharides
  • Mice
  • NF-kappa B / immunology
  • NLR Family, Pyrin Domain-Containing 3 Protein / immunology*
  • Reactive Oxygen Species / immunology*
  • Thioredoxins / immunology*

Substances

  • Carrier Proteins
  • Inflammasomes
  • Lipopolysaccharides
  • NF-kappa B
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Reactive Oxygen Species
  • Txnip protein, mouse
  • Thioredoxins