P2X7 receptor induces mitochondrial failure in monocytes and compromises NLRP3 inflammasome activation during sepsis.
Adult
Aged
Aged, 80 and over
Animals
Disease Models, Animal
Female
Follow-Up Studies
Humans
Hypoxia-Inducible Factor 1, alpha Subunit
/ immunology
Inflammasomes
/ immunology
Macrophages
/ immunology
Male
Mice
Middle Aged
Mitochondria
/ immunology
Mitochondrial Dynamics
/ immunology
Monocytes
/ cytology
NLR Family, Pyrin Domain-Containing 3 Protein
/ immunology
Receptors, Purinergic P2X7
/ immunology
Sepsis
/ blood
Up-Regulation
/ immunology
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
20 06 2019
20 06 2019
Historique:
received:
01
08
2018
accepted:
13
05
2019
entrez:
22
6
2019
pubmed:
22
6
2019
medline:
10
7
2019
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 31221993
doi: 10.1038/s41467-019-10626-x
pii: 10.1038/s41467-019-10626-x
pmc: PMC6586640
doi:
Substances chimiques
HIF1A protein, human
0
Hif1a protein, mouse
0
Hypoxia-Inducible Factor 1, alpha Subunit
0
Inflammasomes
0
NLR Family, Pyrin Domain-Containing 3 Protein
0
NLRP3 protein, human
0
Nlrp3 protein, mouse
0
P2RX7 protein, human
0
P2rx7 protein, mouse
0
Receptors, Purinergic P2X7
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2711Subventions
Organisme : Ministry of Economy and Competitiveness | Instituto de Salud Carlos III (Institute of Health Carlos III)
ID : CD13/00059
Pays : International
Organisme : Ministry of Economy and Competitiveness | Instituto de Salud Carlos III (Institute of Health Carlos III)
ID : PI13/00174
Pays : International
Organisme : EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: "Ideas" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013))
ID : 614578
Pays : International
Organisme : Ministerio de Economía, Industria y Competitividad, Gobierno de España (Ministerio de Economía, Industria y Competitividad)
ID : SAF2017-88276-R
Pays : International
Organisme : European Cooperation in Science and Technology (COST)
ID : BM-1406
Pays : International
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