Sex-specific activation of platelet purinergic signaling is key in local cytokine release and phagocytosis in the peritoneal cavity in intra-abdominal sepsis.

Intra-abdominal sepsis is a life-threatening complex syndrome caused by microbes in the gut microbiota invading the peritoneal cavity. It is one of the major complications of intra-abdominal surgery. To date, only supportive therapies are available. No studies have investigated the progression of intra-abdominal sepsis in the peritoneal cavity. Our group has shown that platelets play an essential role during sepsis, and blocking purinergic signaling in platelets through P2Y and P2Y antagonism significantly lowered inflammatory levels and improved survival in a murine model of sepsis. Here, we tested whether antagonizing purinergic signaling in platelets in the peritoneal cavity can reduce the local release of cytokines and modulate platelet interaction with the immune system. We used cecal ligation and puncture (CLP) to induce sepsis followed by intraperitoneal administration of MRS2279 (P2Y antagonist) or ticagrelor (P2Y antagonist) in male and female mice. The peritoneal cavity fluid (PCF) was collected 4 or 24 h post-CLP and analyzed for cell recruitment, platelet markers, cytokines, and platelet immune cell interactions. Platelet markers were increased 24 h after CLP, although the total platelet count in the peritoneal cavity was lower than the blood. Blocking P2Y or P2Y improved bacterial clearance in the PCF in a sex-dependent manner. The influx of immune cells in the peritoneal cavity was altered by blocking P2Y or P2Y sex-dependently. Blocking P2Y and P2Y receptors can enhance the phagocytic activity in the peritoneal cavity in a sex- and time-related manner, and platelets significantly contribute to the development and progression of sepsis in the peritoneal cavity. Intra-abdominal sepsis is a challenging complication postabdominal surgery caused by perforations of the gastrointestinal tract where microbes invade the peritoneal cavity. This leads to local cytokine release and immune cell dysfunction. Our data identify platelets as key players in mediating inflammation in intra-abdominal sepsis. We have shown that blocking purinergic signaling in the peritoneal cavity reduced cytokine release and cell-cell interactions differently in males and females, hence a sex-specific strategy to improve intra-abdominal sepsis.