Connexin-43-dependent ATP release mediates macrophage activation during sepsis

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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 Lyz2^cre/creGja1^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 signaling on macrophages improves sepsis outcome.

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All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

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Michel Dosch

Department for BioMedical Research, University of Bern, Bern, Switzerland

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-4087-4293
Joël Zindel

Department for BioMedical Research, University of Bern, Bern, Switzerland

Competing interests
The authors declare that no competing interests exist.
Fadi Jebbawi

Department for BioMedical Research, University of Bern, Bern, Switzerland

Competing interests
The authors declare that no competing interests exist.
Nicolas Melin

Department for BioMedical Research, University of Bern, Bern, Switzerland

Competing interests
The authors declare that no competing interests exist.
Daniel Sanchez-Taltavull

Department for BioMedical Research, University of Bern, Bern, Switzerland

Competing interests
The authors declare that no competing interests exist.
Deborah Stroka

Department for BioMedical Research, University of Bern, Bern, Switzerland

Competing interests
The authors declare that no competing interests exist.
Daniel Candinas

Department for BioMedical Research, University of Bern, Bern, Switzerland

Competing interests
The authors declare that no competing interests exist.
Guido Beldi

Department for BioMedical Research, University of Bern, Bern, Switzerland

For correspondence
guido.beldi@insel.ch

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-9914-3807

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).

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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.