In:
eLife, eLife Sciences Publications, Ltd, Vol. 8 ( 2019-02-08)
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.
Type of Medium:
Online Resource
ISSN:
2050-084X
DOI:
10.7554/eLife.42670.001
DOI:
10.7554/eLife.42670.002
DOI:
10.7554/eLife.42670.003
DOI:
10.7554/eLife.42670.004
DOI:
10.7554/eLife.42670.005
DOI:
10.7554/eLife.42670.006
DOI:
10.7554/eLife.42670.007
DOI:
10.7554/eLife.42670.008
DOI:
10.7554/eLife.42670.009
DOI:
10.7554/eLife.42670.010
DOI:
10.7554/eLife.42670.011
DOI:
10.7554/eLife.42670.012
DOI:
10.7554/eLife.42670.013
DOI:
10.7554/eLife.42670.014
DOI:
10.7554/eLife.42670.015
DOI:
10.7554/eLife.42670.016
DOI:
10.7554/eLife.42670.017
DOI:
10.7554/eLife.42670.018
DOI:
10.7554/eLife.42670.019
DOI:
10.7554/eLife.42670.020
DOI:
10.7554/eLife.42670.022
DOI:
10.7554/eLife.42670.023
Language:
English
Publisher:
eLife Sciences Publications, Ltd
Publication Date:
2019
detail.hit.zdb_id:
2687154-3
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