PT  - JOURNAL ARTICLE
AU  - Michel Dosch
AU  - Joël Zindel
AU  - Fadi Jebbawi
AU  - Nicolas Melin
AU  - Daniel Sanchez-Taltavull
AU  - Deborah Stroka
AU  - Daniel Candinas
AU  - Guido Beldi
TI  - Connexin-43 dependent ATP release mediates macrophage activation during peritonitis
AID  - 10.1101/424333
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 424333
4099  - http://biorxiv.org/content/early/2018/09/23/424333.short
4100  - http://biorxiv.org/content/early/2018/09/23/424333.full
AB  - Peritonitis is the consequence of bacterial spillage into a sterile environment by gastrointestinal hollow-organ perforation that may lead to fulminant sepsis. Outcome of peritonitis-induced sepsis critically depends on macrophage activation by extracellular ATP release and associated para- and autocrine signaling via purinergic receptors. Mechanisms that mediate and control ATP release, however, are poorly understood. Here we show that TLR-2 and -4 agonists trigger ATP release via Connexin-43 (CX43) hemichannels in peritoneal macrophages leading to poor survival during sepsis. In humans, CX43 expression was upregulated on macrophages isolated from the peritoneal cavity in patients with intraperitoneal infection but not in healthy controls. Using a murine caecal ligation and puncture (CLP) model, we identified increased CX43 expression in activated infiltrating peritoneal, hepatic and pulmonary macrophages. Conditional MAC-CX43 KO Lyz2cre/creCx43flox/flox mice were developed to specifically assess the CX43 impact in macrophages. Both macrophage-specific CX43 deletion (using Lyz2cre/creCx43flox/flox mice) or pharmacological CX43 blockade were associated with reduced cytokine secretion by macrophages in response to LPS and CLP. This was ultimately resulting in increased survival in Lyz2cre/creCx43flox/flox mice and after pharmacological blockade. Specific inhibition of the purinergic receptor P2RY1 abrogated CX43 elicited cytokine responses. In conclusion, inhibition of autocrine ATP signaling via CX43 on macrophages and P2RY1 improves sepsis outcome in experimental peritonitis.Brief Summary Connexin-43-mediated ATP release from macrophages in response to TLR-4 and -2 agonists modulates autocrine activation of macrophages in a P2Y1-dependent manner, ultimately determining sepsis survival.