CD39 Is a Negative Regulator of P2X7-mediated Inflammatory Cell Death in Mast Cells

Cell Commun Signal. 2014 Jul 16;12:40. doi: 10.1186/s12964-014-0040-3.

Abstract

Background: Mast cells (MCs) are major contributors to an inflammatory milieu. One of the most potent drivers of inflammation is the cytokine IL-1β, which is produced in the cytoplasm in response to danger signals like LPS. Several controlling mechanisms have been reported which limit the release of IL-1β. Central to this regulation is the NLRP3 inflammasome, activation of which requires a second danger signal with the capacity to subvert the homeostasis of lysosomes and mitochondria. High concentrations of extracellular ATP have the capability to perturb the plasma membrane by activation of P2X7 channels and serve as such a danger signal. In this study we investigate the role of P2X7 channels and the ecto-5'-nucleotidase CD39 in ATP-triggered release of IL-1β from LPS-treated mast cells.

Results: We report that in MCs CD39 sets an activation threshold for the P2X7-dependent inflammatory cell death and concomitant IL-1β release. Knock-out of CD39 or stimulation with non-hydrolysable ATP led to a lower activation threshold for P2X7-dependent responses. We found that stimulation of LPS-primed MCs with high doses of ATP readily induced inflammatory cell death. Yet, cell death-dependent release of IL-1β yielded only minute amounts of IL-1β. Intriguingly, stimulation with low ATP concentrations augmented the production of IL-1β in LPS-primed MCs in a P2X7-independent but caspase-1-dependent manner.

Conclusion: Our study demonstrates that the fine-tuned interplay between ATP and different surface molecules recognizing or modifying ATP can control inflammatory and cell death decisions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Antigens, CD / metabolism*
  • Apyrase / metabolism*
  • Bone Marrow Cells / metabolism*
  • Bone Marrow Cells / pathology
  • Caspase 1 / metabolism
  • Cell Death
  • Cells, Cultured
  • Inflammation / metabolism
  • Inflammation / pathology
  • Interleukin-1beta / metabolism
  • Lipopolysaccharides / pharmacology
  • Male
  • Mast Cells / metabolism*
  • Mast Cells / pathology
  • Mice
  • Receptors, Purinergic P2X7 / metabolism*

Substances

  • Antigens, CD
  • Interleukin-1beta
  • Lipopolysaccharides
  • Receptors, Purinergic P2X7
  • Adenosine Triphosphate
  • Caspase 1
  • Apyrase
  • CD39 antigen