Anales RANF

S20-01 P2X7 RECEPTOR EXPRESSION AND FUNCTION IN HUMAN SEPSIS Pablo Pelegrín Biomedical Research Institute of Murcia (IMIB-Arrixaca), 30120 Murcia, Spain. Sepsis characterises by a systemic inflammatory response that is followed by an immunosuppression of the host. Metabolic defects and mitochondrial failure are common in immunocompromised septic patients. The NLRP3 inflammasome is important for establishing an inflammatory response after activation by the purinergic P2X7 receptor. Here, we study a cohort of individuals with intra-abdominal origin sepsis and show that patient monocytes have impaired NLRP3 activation by the P2X7 receptor. Furthermore, most sepsis-related deaths are among patients whose NLRP3 activation is profoundly altered. In monocytes from septic patients, the P2X7 receptor is associated with mitochondrial dysfunction; moreover, activation of the P2X7 receptor results in mitochondrial damage, which in turn inhibits NLRP3 activation by HIF-1 ฀. We also show that mortality increases in a mouse model of sepsis when the P2X7 receptor is activated in vivo. Our data reveal a molecular mechanism initiated by the P2X7 receptor that contributes to NLRP3 impairment during infection.