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.

Details

Title
P2X7 receptor induces mitochondrial failure in monocytes and compromises NLRP3 inflammasome activation during sepsis
Author
Martínez-García, Juan José 1 ; Martínez-Banaclocha, Helios 1 ; Angosto-Bazarra, Diego 1 ; Carlos de Torre-Minguela 1   VIAFID ORCID Logo  ; Baroja-Mazo, Alberto 1 ; Alarcón-Vila, Cristina 1 ; Martínez-Alarcón, Laura 1 ; Amores-Iniesta, Joaquín 1 ; Martín-Sánchez, Fátima 1 ; Ercole, Giovanni A 2 ; Martínez, Carlos M 3   VIAFID ORCID Logo  ; González-Lisorge, Ada 2   VIAFID ORCID Logo  ; Fernández-Pacheco, José 2 ; Martínez-Gil, Piedad 2 ; Adriouch, Sahil 4   VIAFID ORCID Logo  ; Koch-Nolte, Friedrich 5 ; Luján, Juan 6 ; Acosta-Villegas, Francisco 2 ; Parrilla, Pascual 7 ; García-Palenciano, Carlos 2 ; Pelegrin, Pablo 1   VIAFID ORCID Logo 

 Unidad de Inflamación Molecular y Cirugía Experimental, Instituto Murciano de Investigación Biosanitaria IMIB-Arrixaca, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain 
 Unidad de Reanimación, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain 
 Plataforma de Patología, Instituto Murciano de Investigación Biosanitaria IMIB-Arrixaca, Murcia, Spain 
 Normandie University, UNIROUEN, INSERM, U1234, Rouen, France 
 Institute of Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany 
 Servicio de Cirugía General, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain 
 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 
Pages
1-14
Publication year
2019
Publication date
Jun 2019
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2244139253
Copyright
© 2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.