title: P2X7 Receptor Signaling Contributes to Sepsis-Associated Brain Dysfunction.
abstract: Sepsis results in unfettered inflammation, tissue damage, and multiple organ failure. Diffuse brain dysfunction and neurological manifestations secondary to sepsis are termed sepsis-associated encephalopathy (SAE). Extracellular nucleotides, proinflammatory cytokines, and oxidative stress reactions are associated with delirium and brain injury, and might be linked to the pathophysiology of SAE. P2X7 receptor activation by extracellular ATP leads to maturation and release of IL-1β by immune cells, which stimulates the production of oxygen reactive species. Hence, we sought to investigate the role of purinergic signaling by P2X7 in a model of sepsis. We also determined how this process is regulated by the ectonucleotidase CD39, a scavenger of extracellular nucleotides. Wild type (WT), P2X7 receptor (P2X7-/-), or CD39 (CD39-/-) deficient mice underwent sham laparotomy or CLP induced by ligation and puncture of the cecum. We noted that genetic deletion of P2X7 receptor decreased markers of oxidative stress in murine brains 24 h after sepsis induction. The pharmacological inhibition or genetic ablation of the P2X7 receptor attenuated the IL-1β and IL-6 production in the brain from septic mice. Furthermore, our results suggest a crucial role for the enzyme CD39 in limiting P2X7 receptor proinflammatory responses since CD39-/-septic mice exhibited higher levels of IL-1β in the brain. We have also demonstrated that P2X7 receptor blockade diminished STAT3 activation in cerebral cortex and hippocampus from septic mice, indicating association of ATP-P2X7-STAT3 signaling axis in SAE during sepsis. Our findings suggest that P2X7 receptor might serve as a suitable therapeutic target to ameliorate brain damage in sepsis.
authors.affiliation: Laboratory of Immunophysiology, Biophysics Institute Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.|Department of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Harvard University, Boston, MA, USA.
authors.forename: Luiz Eduardo Baggio
authors.initials: LEB
authors.lastname: Savio
authors.affiliation: Laboratory of Immunophysiology, Biophysics Institute Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Mariana G Juste
authors.initials: MGJ
authors.lastname: Andrade
authors.affiliation: Department of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Harvard University, Boston, MA, USA.|Laboratory of Biochemical and Cytological Analysis, Faculty of Pharmacy, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: Paola
authors.initials: P
authors.lastname: de Andrade Mello
authors.affiliation: Laboratory of Immunophysiology, Biophysics Institute Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Patrícia Teixeira
authors.initials: PT
authors.lastname: Santana
authors.affiliation: Laboratory of Immunophysiology, Biophysics Institute Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Aline Cristina Abreu
authors.initials: ACA
authors.lastname: Moreira-Souza
authors.affiliation: Laboratory of Neuroprotection and Metabolic Diseases, Department of Biochemistry, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Janaína
authors.initials: J
authors.lastname: Kolling
authors.affiliation: Laboratory of Neuroprotection and Metabolic Diseases, Department of Biochemistry, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Aline
authors.initials: A
authors.lastname: Longoni
authors.affiliation: Department of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Harvard University, Boston, MA, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Feldbrügge
authors.affiliation: Department of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Harvard University, Boston, MA, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Laboratory of Neuroprotection and Metabolic Diseases, Department of Biochemistry, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Angela T S
authors.initials: ATS
authors.lastname: Wyse
authors.affiliation: Department of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Harvard University, Boston, MA, USA.
authors.forename: Simon C
authors.initials: SC
authors.lastname: Robson
authors.affiliation: Laboratory of Immunophysiology, Biophysics Institute Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. rcsilva@biof.ufrj.br.|Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Edifício do Centro de Ciências da Saúde, Bloco G. Av. Carlos Chagas Filho, 373, Cidade Universitária, Ilha do Fundão, Rio de Janeiro, RJ, 21941-902, Brazil. rcsilva@biof.ufrj.br.
authors.forename: Robson
authors.identifier: http://orcid.org/0000-0002-7318-0204
authors.initials: R
authors.lastname: Coutinho-Silva
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D001081:Apyrase / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002374:Catalase / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000502:physiology; D058486:Receptors, Purinergic P2X7 / Q000235:genetics / Q000378:metabolism*; D018805:Sepsis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics*; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D016207:Cytokines; D058486:Receptors, Purinergic P2X7; D002374:Catalase; D013482:Superoxide Dismutase; D001081:Apyrase; C067869:CD39 antigen
keywords: Brain; CD39; Il-1β; P2X7 receptor; STAT3; Sepsis