1. P2X7 receptor induces mitochondrial failure in monocytes and compromises NLRP3 inflammasome activation during sepsis.
- Author
-
Martínez-García JJ, Martínez-Banaclocha H, Angosto-Bazarra D, de Torre-Minguela C, Baroja-Mazo A, Alarcón-Vila C, Martínez-Alarcón L, Amores-Iniesta J, Martín-Sánchez F, Ercole GA, Martínez CM, González-Lisorge A, Fernández-Pacheco J, Martínez-Gil P, Adriouch S, Koch-Nolte F, Luján J, Acosta-Villegas F, Parrilla P, García-Palenciano C, and Pelegrin P
- Subjects
- Adult, Aged, Aged, 80 and over, Animals, Disease Models, Animal, Female, Follow-Up Studies, Humans, Hypoxia-Inducible Factor 1, alpha Subunit immunology, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Inflammasomes metabolism, Macrophages immunology, Macrophages metabolism, Male, Mice, Middle Aged, Mitochondria immunology, Mitochondria metabolism, Mitochondrial Dynamics immunology, Monocytes cytology, NLR Family, Pyrin Domain-Containing 3 Protein immunology, Receptors, Purinergic P2X7 immunology, Sepsis blood, Sepsis microbiology, Sepsis mortality, Up-Regulation immunology, Inflammasomes immunology, Monocytes immunology, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, Receptors, Purinergic P2X7 metabolism, Sepsis immunology
- 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.
- Published
- 2019
- Full Text
- View/download PDF