Neutrophil P2X7 receptors mediate NLRP3 inflammasome-dependent IL-1β secretion in response to ATP

Nat Commun. 2016 Feb 15;7:10555. doi: 10.1038/ncomms10555.

Abstract

Although extracellular ATP is abundant at sites of inflammation, its role in activating inflammasome signalling in neutrophils is not well characterized. In the current study, we demonstrate that human and murine neutrophils express functional cell-surface P2X7R, which leads to ATP-induced loss of intracellular K(+), NLRP3 inflammasome activation and IL-1β secretion. ATP-induced P2X7R activation caused a sustained increase in intracellular [Ca(2+)], which is indicative of P2X7R channel opening. Although there are multiple polymorphic variants of P2X7R, we found that neutrophils from multiple donors express P2X7R, but with differential efficacies in ATP-induced increase in cytosolic [Ca(2+)]. Neutrophils were also the predominant P2X7R-expressing cells during Streptococcus pneumoniae corneal infection, and P2X7R was required for bacterial clearance. Given the ubiquitous presence of neutrophils and extracellular ATP in multiple inflammatory conditions, ATP-induced P2X7R activation and IL-1β secretion by neutrophils likely has a significant, wide ranging clinical impact.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / immunology*
  • Animals
  • Blotting, Western
  • Calcium / metabolism
  • Carrier Proteins / genetics
  • Carrier Proteins / immunology*
  • Disease Models, Animal
  • Enzyme-Linked Immunosorbent Assay
  • Eye Infections, Bacterial / immunology
  • Flow Cytometry
  • Humans
  • Inflammasomes / immunology*
  • Interleukin-1beta / metabolism*
  • Keratitis / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microscopy, Fluorescence
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Neutrophils / drug effects
  • Neutrophils / immunology*
  • Neutrophils / metabolism
  • Potassium / metabolism
  • Purinergic P2X Receptor Antagonists / pharmacology
  • Receptors, Purinergic P2X7 / immunology*
  • Spectrophotometry, Atomic
  • Streptococcal Infections / immunology

Substances

  • Carrier Proteins
  • IL1B protein, human
  • IL1B protein, mouse
  • Inflammasomes
  • Interleukin-1beta
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • Nlrp3 protein, mouse
  • Purinergic P2X Receptor Antagonists
  • Receptors, Purinergic P2X7
  • Adenosine Triphosphate
  • Potassium
  • Calcium