P2X7 receptor induces mitochondrial failure in monocytes and compromises NLRP3 inflammasome activation during sepsis - Normandie Université Access content directly
Journal Articles Nature Communications Year : 2019

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

Juan José Martínez-García
  • Function : Author
Helios Martínez-Banaclocha
  • Function : Author
Diego Angosto-Bazarra
  • Function : Author
Carlos de Torre-Minguela
  • Function : Author
Alberto Baroja-Mazo
  • Function : Author
Cristina Alarcón-Vila
  • Function : Author
Laura Martínez-Alarcón
  • Function : Author
Joaquín Amores-Iniesta
  • Function : Author
Fátima Martín-Sánchez
  • Function : Author
Giovanni A Ercole
  • Function : Author
Carlos M Martínez
  • Function : Author
Ada González-Lisorge
  • Function : Author
José Fernández-Pacheco
  • Function : Author
Piedad Martínez-Gil
  • Function : Author
Juan Luján
  • Function : Author
Francisco Acosta-Villegas
  • Function : Author
Pascual Parrilla
  • Function : Author
Carlos García-Palenciano
  • Function : Author
Pablo Pelegrin

Abstract

Sepsis is characterized by a systemic inflammatory response followed by immunosuppres-sion of the host. Metabolic defects and mitochondrial failure are common in immunocom-promised 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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Dates and versions

hal-02376247 , version 1 (22-11-2019)

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Juan José Martínez-García, Helios Martínez-Banaclocha, Diego Angosto-Bazarra, Carlos de Torre-Minguela, Alberto Baroja-Mazo, et al.. P2X7 receptor induces mitochondrial failure in monocytes and compromises NLRP3 inflammasome activation during sepsis. Nature Communications, 2019, 10 (1), ⟨10.1038/s41467-019-10626-x⟩. ⟨hal-02376247⟩
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