P2X7 receptor induces mitochondrial failure in monocytes and compromises NLRP3 inflammasome activation during sepsis

Juan José Martínez-García, Helios Martínez-Banaclocha, Diego Angosto-Bazarra, Carlos de Torre-Minguela, Alberto Baroja-Mazo, Cristina Alarcón-Vila, Laura Martínez-Alarcón, Joaquín Amores-Iniesta, Fátima Martín-Sánchez, Giovanni A. Ercole, Carlos M. Martínez, Ada González-Lisorge, José Fernández-Pacheco, Piedad Martínez-Gil, Sahil Adriouch, Friedrich Koch-Nolte, Juan Luján, Francisco Acosta-Villegas, Pascual Parrilla, Carlos García-Palenciano and Pablo Pelegrin ()
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Juan José Martínez-García: Hospital Clínico Universitario Virgen de la Arrixaca
Helios Martínez-Banaclocha: Hospital Clínico Universitario Virgen de la Arrixaca
Diego Angosto-Bazarra: Hospital Clínico Universitario Virgen de la Arrixaca
Carlos de Torre-Minguela: Hospital Clínico Universitario Virgen de la Arrixaca
Alberto Baroja-Mazo: Hospital Clínico Universitario Virgen de la Arrixaca
Cristina Alarcón-Vila: Hospital Clínico Universitario Virgen de la Arrixaca
Laura Martínez-Alarcón: Hospital Clínico Universitario Virgen de la Arrixaca
Joaquín Amores-Iniesta: Hospital Clínico Universitario Virgen de la Arrixaca
Fátima Martín-Sánchez: Hospital Clínico Universitario Virgen de la Arrixaca
Giovanni A. Ercole: Hospital Clínico Universitario Virgen de la Arrixaca
Carlos M. Martínez: Instituto Murciano de Investigación Biosanitaria IMIB-Arrixaca
Ada González-Lisorge: Hospital Clínico Universitario Virgen de la Arrixaca
José Fernández-Pacheco: Hospital Clínico Universitario Virgen de la Arrixaca
Piedad Martínez-Gil: Hospital Clínico Universitario Virgen de la Arrixaca
Sahil Adriouch: INSERM, U1234
Friedrich Koch-Nolte: University Medical Center Hamburg-Eppendorf
Juan Luján: Hospital Clínico Universitario Virgen de la Arrixaca
Francisco Acosta-Villegas: Hospital Clínico Universitario Virgen de la Arrixaca
Pascual Parrilla: Hospital Clínico Universitario Virgen de la Arrixaca
Carlos García-Palenciano: Hospital Clínico Universitario Virgen de la Arrixaca
Pablo Pelegrin: Hospital Clínico Universitario Virgen de la Arrixaca

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-10626-x

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