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Abstract
Sepsis is characterized by a systemic inflammatory response followed by immunosuppression of the host. Metabolic defects and mitochondrial failure are common in immunocompromised patients with sepsis. 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 sepsis patients, the P2X7 receptor is associated with mitochondrial dysfunction. Furthermore, activation of the P2X7 receptor results in mitochondrial damage, which in turn inhibits NLRP3 activation by HIF-1α. We show that mortality increases in a mouse model of sepsis when the P2X7 receptor is activated in vivo. These data reveal a molecular mechanism initiated by the P2X7 receptor that contributes to NLRP3 impairment during infection.
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1 Unidad de Inflamación Molecular y Cirugía Experimental, Instituto Murciano de Investigación Biosanitaria IMIB-Arrixaca, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain
2 Unidad de Reanimación, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain
3 Plataforma de Patología, Instituto Murciano de Investigación Biosanitaria IMIB-Arrixaca, Murcia, Spain
4 Normandie University, UNIROUEN, INSERM, U1234, Rouen, France
5 Institute of Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
6 Servicio de Cirugía General, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain
7 Unidad de Inflamación Molecular y Cirugía Experimental, Instituto Murciano de Investigación Biosanitaria IMIB-Arrixaca, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain; Servicio de Cirugía General, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain