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

Dosch, Michel; Zindel, Joël; Jebbawi, Fadi; Melin, Nicolas; Sanchez-Taltavull, Daniel; Stroka, Deborah; Candinas, Daniel; Beldi, Guido (2019). Connexin-43-dependent ATP release mediates macrophage activation during sepsis. eLife, 8 10.7554/eLife.42670

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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 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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Viszeralchirurgie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Viszeralchirurgie

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR)

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Dosch, Michel Ernest Jean-Pierre; Jebbawi, Fadi; Melin, Nicolas; Sánchez Taltavull, Daniel; Keogh-Stroka, Deborah M.; Candinas, Daniel and Beldi, Guido

Subjects:

600 Technology > 610 Medicine & health

ISSN:

2050-084X

Language:

English

Submitter:

Lilian Karin Smith-Wirth

Date Deposited:

07 Feb 2020 15:30

Last Modified:

07 Feb 2020 15:30

Publisher DOI:

10.7554/eLife.42670

PubMed ID:

30735126

Uncontrolled Keywords:

ATP release Connexin-43 human immunology infectious disease inflammation macrophages microbiology mouse purinergic signaling sepsis

BORIS DOI:

10.7892/boris.139431

URI:

https://boris.unibe.ch/id/eprint/139431

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