P2X7 Receptor Signaling Contributes to Sepsis-Associated Brain Dysfunction

• Published in: Molecular neurobiology Vol. 54; no. 8; pp. 6459 - 6470
• Main Authors: Savio, Luiz Eduardo Baggio, Andrade, Mariana G. Juste, de Andrade Mello, Paola, Santana, Patrícia Teixeira, Moreira-Souza, Aline Cristina Abreu, Kolling, Janaína, Longoni, Aline, Feldbrügge, Linda, Wu, Yan, Wyse, Angela T. S., Robson, Simon C., Coutinho-Silva, Robson
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.10.2017; Springer Nature B.V
• Subjects: Ablation; Activation; Animals; Antigens, CD - genetics; Antigens, CD - metabolism; Apyrase - genetics; Apyrase - metabolism; ATP; Biomedical and Life Sciences; Biomedicine; Brain; Brain - metabolism; Brain - pathology; Brain damage; Brain injury; Catalase - metabolism; Cecum; Cell Biology; Cerebral cortex; Cerebrum; Clonal deletion; Cytokines; Cytokines - metabolism; Ectonucleotidase; Encephalopathy; Inflammation; Inflammation - genetics; Inflammation - metabolism; Inflammation - pathology; Interleukin 1; Interleukin 6; Male; Mental disorders; Mice; Mice, Knockout; Neurobiology; Neurology; Neurons; Neurosciences; Nucleotides; Oxidative stress; Oxidative Stress - physiology; Receptor mechanisms; Receptors, Purinergic P2X7 - genetics; Receptors, Purinergic P2X7 - metabolism; Rodents; Sepsis; Sepsis - genetics; Sepsis - metabolism; Sepsis - pathology; Signal Transduction - genetics; Signaling; Stat3 protein; Superoxide Dismutase - metabolism; CD39; Brain; Sepsis; P2X7 receptor; Il-1β; STAT3
• ISSN: 0893-7648; 1559-1182
• DOI: 10.1007/s12035-016-0168-9

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.