Journal
ELIFE
Volume 8, Issue -, Pages -Publisher
eLIFE SCIENCES PUBL LTD
DOI: 10.7554/eLife.42670
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Funding
- Schweizerischer Nationalfonds zur Forderung der Wissenschaftlichen Forschung [323530_158117, 146986]
- Novartis Stiftung fur Medizinisch-Biologische Forschung [14C160]
- University of Bern Interdisciplinary Grant
- Schweizerischer Nationalfonds senschaftlichen Forschungzur Forderung der Wissenschaftlichen Forschung [166594]
- Swiss National Science Foundation (SNF) [323530_158117] Funding Source: Swiss National Science Foundation (SNF)
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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 xx macrophages. Conditional Lyz2(cre/cre)Gja1(flox/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.
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