Connexin-43-dependent ATP release mediates macrophage activation during sepsis
- University of Bern, Switzerland
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 signaling 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. onditional 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 signaling on macrophages improves sepsis outcome.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
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Author details
Funding
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (323530_158117)
- Michel Dosch
Novartis Stiftung für Medizinisch-Biologische Forschung (14C160)
- Michel Dosch
- Guido Beldi
University of Bern (Interdisciplinary Grant)
- Guido Beldi
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (166594)
- Guido Beldi
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (146986)
- Guido Beldi
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Animal experiments were planned, carried out and reported in agreement with current 3R and ARRIVE guidelines (Kilkenny et al., 2010) and approved according to Swiss animal protection laws by the Veterinary Authorities of the Canton Bern, Switzerland (license no. BE 4/15).
Human subjects: All human studies were approved by the Ethical Commission of the Canton Bern and written informed consent was obtained from all subjects. Peritoneal fluid collection at the beginning of an operation was included in a larger clinical trial, whose protocol is published on ClinicalTrials.gov (NCT03554148, Study ID Number: 2017-00573).
Copyright
© 2019, Dosch et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Connexin-43-dependent ATP release mediates macrophage activation during sepsis
eLife 8:e42670.
https://doi.org/10.7554/eLife.42670
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