Sex‐related differences in how hyperactive platelets exacerbate the cytokine storm in the peritoneal cavity during intra‐abdominal sepsis

Abstract

Intra‐abdominal sepsis, a complex clinical syndrome resulting from a serious infection, is a major healthcare problem associated with high morbidity and mortality. Inflammatory cytokine levels in the peritoneal cavity (PC) are much higher than in blood, and the enhanced release of these mediators is a key participant to the deleterious effects of sepsis. Platelets are well‐known for their role in modulating proinflammatory cytokine secretion. We have previously shown that in vivo blockade of P2Y12 signaling, an important regulator for platelet secretion, resulted in lower inflammatory cytokines in the blood. We hypothesize that proinflammatory cytokine levels in the peritoneal cavity will be elevated in a murine model of sepsis. To this end, male and female mice underwent a cecal ligation and puncture (CLP) procedure to induce sepsis and were treated with ticagrelor to block P2Y12 signaling. Peritoneal cavity cells and fluid (PCF) were collected 24 hrs post‐surgery to measure changes in proinflammatory cytokine levels and immune cell interactions. Our data show that during CLP‐induced sepsis, PCF exhibited very low platelet counts and platelet‐immune cell aggregates compared to sham‐treated mice irrespective of sex (*p £ 0.05, n=4). Surprisingly, despite low platelet numbers, soluble p‐selectin and PF‐4 levels were elevated, indicative of platelet secretion. Moreover, P2Y12 antagonist treatment significantly decreased platelet markers and immune cell aggregates in PCF from male but not female mice (*p £ 0.05, n=5). In conclusion, intercellular communication mediated through systemic platelet activation influences the peritoneal cavity during intra‐abdominal sepsis, even in the absence of platelets locally in a sex‐related manner.Moreover, P2Y12 antagonist treatment significantly decreased platelet markers and immune cell aggregates in PCF from male but not female mice. In conclusion, intercellular communication mediated through systemic platelet activation influences the peritoneal cavity during intra‐abdominal sepsis, even in the absence of platelets locally in a sex‐related manner.