| First Author | Dosch M | Year | 2019 |
| Journal | Elife | Volume | 8 |
| PubMed ID | 30735126 | Mgi Jnum | J:275972 |
| Mgi Id | MGI:6304068 | Doi | 10.7554/eLife.42670 |
| Citation | Dosch M, et al. (2019) Connexin-43-dependent ATP release mediates macrophage activation during sepsis. Elife 8:e42670 |
| abstractText | 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 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. |
