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 P2Y₁ and P2Y₁₂ 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 (P2Y₁ antagonist) or Ticagrelor (P2Y₁₂ antagonist) in male and female mice. The peritoneal cavity fluid (PCF) was collected 4- or 24-hours post-CLP and analyzed for cell recruitment, platelet markers, cytokines, and platelet immune cell interactions. Platelet markers were increased 24 hours after CLP, although the total platelet count in the peritoneal cavity was lower than the blood. Blocking P2Y₁₂ or P2Y₁ improved bacterial clearance in the PCF in a sex-dependent manner. The influx of immune cells in the peritoneal cavity was altered by blocking P2Y₁₂ or P2Y₁ sex-dependently. Blocking P2Y₁ and P2Y₁₂ 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.