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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 \u22124 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.<\/jats:p>","DOI":"10.7554\/elife.42670","type":"journal-article","created":{"date-parts":[[2019,2,8]],"date-time":"2019-02-08T08:00:16Z","timestamp":1549612816000},"source":"Crossref","is-referenced-by-count":101,"title":["Connexin-43-dependent ATP release mediates macrophage activation during sepsis"],"prefix":"10.7554","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4087-4293","authenticated-orcid":true,"given":"Michel","family":"Dosch","sequence":"first","affiliation":[{"name":"Department for BioMedical Research, University of Bern, Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jo\u00ebl","family":"Zindel","sequence":"additional","affiliation":[{"name":"Department for BioMedical Research, University of Bern, Bern, 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