Connexin-43-dependent ATP release mediates macrophage activation during sepsis.
Publisher DOI
PubMed ID
30735126
Abstract
Bacterial spillage into a sterile environment following intestinal hollow-organ perforation leads to peritonitis and fulminant sepsis. Outcome of sepsis critically depends on macrophage activation by extracellular ATP-release and associated autocrine signalling via purinergic receptors. ATP-release mechanisms, however, are poorly understood. Here, we show that TLR-2 and -4 agonists trigger ATP-release via Connexin-43 hemichannels in macrophages leading to poor sepsis survival. In humans, Connexin-43 was upregulated on macrophages isolated from the peritoneal cavity in patients with peritonitis but not in healthy controls. Using a murine peritonitis/sepsis model, we identified increased Connexin-43 expression in peritoneal and hepatic macrophages. Conditional Lyz2cre/creGja1flox/flox mice were developed to specifically assess Connexin-43 impact in macrophages. Both macrophage-specific Connexin-43 deletion and pharmacological Connexin-43 blockade were associated with reduced cytokine secretion by macrophages in response to LPS and CLP, ultimately resulting in increased survival. In conclusion, inhibition of autocrine Connexin-43-dependent ATP signalling on macrophages improves sepsis outcome.
Date Issued
2019-02-08
Publication Type
Article
Subject(s)
Subjects
ATP release Connexin-43 human immunology infectious disease inflammation macrophages microbiology mouse purinergic signaling sepsis
Language(s)
en
Author(s)
Zindel, Joël |
Journal
eLife
ISSN
2050-084X
Access(Rights)
open.access