title: Extracellular ATP protects against sepsis through macrophage P2X7 purinergic receptors by enhancing intracellular bacterial killing.
abstract: Extracellular ATP binds to and signals through P2X7 receptors (P2X7Rs) to modulate immune function in both inflammasome-dependent and -independent manners. In this study, P2X7(-/-) mice, the pharmacological agonists ATP-magnesium salt (Mg-ATP; 100 mg/kg, EC50 ≈ 1.32 mM) and benzoylbenzoyl-ATP (Bz-ATP; 10 mg/kg, EC50 ≈ 285 μM), and antagonist oxidized ATP (oxi-ATP; 40 mg/kg, IC50 ≈ 100 μM) were used to show that P2X7R activation is crucial for the control of mortality, bacterial dissemination, and inflammation in cecal ligation and puncture-induced polymicrobial sepsis in mice. Our results with P2X7(-/-) bone marrow chimeric mice, adoptive transfer of peritoneal macrophages, and myeloid-specific P2X7(-/-) mice indicate that P2X7R signaling on macrophages is essential for the protective effect of P2X7Rs. P2X7R signaling protects through enhancing bacterial killing by macrophages, which is independent of the inflammasome. By using the connexin (Cx) channel inhibitor Gap27 (0.1 mg/kg, IC50 ≈ 0.25 μM) and pannexin channel inhibitor probenecid (10 mg/kg, IC50 ≈ 11.7 μM), we showed that ATP release through Cx is important for inhibiting inflammation and bacterial burden. In summary, targeting P2X7Rs provides a new opportunity for harnessing an endogenous protective immune mechanism in the treatment of sepsis.
authors.affiliation: *Department of Surgery and Center for Immunity and Inflammation, Rutgers New Jersey Medical School, Newark, New Jersey, USA; Department of Surgery, Morristown Medical Center, Morristown, New Jersey, USA; Department of Pneumology, Freiburg University Medical Center, Albert-Ludwigs-University, Freiburg, Germany; Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy; Department of Medical Chemistry, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary; and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Balázs
authors.initials: B
authors.lastname: Csóka
authors.affiliation: *Department of Surgery and Center for Immunity and Inflammation, Rutgers New Jersey Medical School, Newark, New Jersey, USA; Department of Surgery, Morristown Medical Center, Morristown, New Jersey, USA; Department of Pneumology, Freiburg University Medical Center, Albert-Ludwigs-University, Freiburg, Germany; Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy; Department of Medical Chemistry, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary; and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Zoltán H
authors.initials: ZH
authors.lastname: Németh
authors.affiliation: *Department of Surgery and Center for Immunity and Inflammation, Rutgers New Jersey Medical School, Newark, New Jersey, USA; Department of Surgery, Morristown Medical Center, Morristown, New Jersey, USA; Department of Pneumology, Freiburg University Medical Center, Albert-Ludwigs-University, Freiburg, Germany; Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy; Department of Medical Chemistry, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary; and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Gábor
authors.initials: G
authors.lastname: Törő
authors.affiliation: *Department of Surgery and Center for Immunity and Inflammation, Rutgers New Jersey Medical School, Newark, New Jersey, USA; Department of Surgery, Morristown Medical Center, Morristown, New Jersey, USA; Department of Pneumology, Freiburg University Medical Center, Albert-Ludwigs-University, Freiburg, Germany; Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy; Department of Medical Chemistry, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary; and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Marco
authors.initials: M
authors.lastname: Idzko
authors.affiliation: *Department of Surgery and Center for Immunity and Inflammation, Rutgers New Jersey Medical School, Newark, New Jersey, USA; Department of Surgery, Morristown Medical Center, Morristown, New Jersey, USA; Department of Pneumology, Freiburg University Medical Center, Albert-Ludwigs-University, Freiburg, Germany; Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy; Department of Medical Chemistry, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary; and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Andreas
authors.initials: A
authors.lastname: Zech
authors.affiliation: *Department of Surgery and Center for Immunity and Inflammation, Rutgers New Jersey Medical School, Newark, New Jersey, USA; Department of Surgery, Morristown Medical Center, Morristown, New Jersey, USA; Department of Pneumology, Freiburg University Medical Center, Albert-Ludwigs-University, Freiburg, Germany; Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy; Department of Medical Chemistry, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary; and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Balázs
authors.initials: B
authors.lastname: Koscsó
authors.affiliation: *Department of Surgery and Center for Immunity and Inflammation, Rutgers New Jersey Medical School, Newark, New Jersey, USA; Department of Surgery, Morristown Medical Center, Morristown, New Jersey, USA; Department of Pneumology, Freiburg University Medical Center, Albert-Ludwigs-University, Freiburg, Germany; Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy; Department of Medical Chemistry, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary; and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Spolarics
authors.affiliation: *Department of Surgery and Center for Immunity and Inflammation, Rutgers New Jersey Medical School, Newark, New Jersey, USA; Department of Surgery, Morristown Medical Center, Morristown, New Jersey, USA; Department of Pneumology, Freiburg University Medical Center, Albert-Ludwigs-University, Freiburg, Germany; Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy; Department of Medical Chemistry, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary; and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Luca
authors.initials: L
authors.lastname: Antonioli
authors.affiliation: *Department of Surgery and Center for Immunity and Inflammation, Rutgers New Jersey Medical School, Newark, New Jersey, USA; Department of Surgery, Morristown Medical Center, Morristown, New Jersey, USA; Department of Pneumology, Freiburg University Medical Center, Albert-Ludwigs-University, Freiburg, Germany; Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy; Department of Medical Chemistry, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary; and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Karolina
authors.initials: K
authors.lastname: Cseri
authors.affiliation: *Department of Surgery and Center for Immunity and Inflammation, Rutgers New Jersey Medical School, Newark, New Jersey, USA; Department of Surgery, Morristown Medical Center, Morristown, New Jersey, USA; Department of Pneumology, Freiburg University Medical Center, Albert-Ludwigs-University, Freiburg, Germany; Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy; Department of Medical Chemistry, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary; and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Katalin
authors.initials: K
authors.lastname: Erdélyi
authors.affiliation: *Department of Surgery and Center for Immunity and Inflammation, Rutgers New Jersey Medical School, Newark, New Jersey, USA; Department of Surgery, Morristown Medical Center, Morristown, New Jersey, USA; Department of Pneumology, Freiburg University Medical Center, Albert-Ludwigs-University, Freiburg, Germany; Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy; Department of Medical Chemistry, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary; and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Pál
authors.initials: P
authors.lastname: Pacher
authors.affiliation: *Department of Surgery and Center for Immunity and Inflammation, Rutgers New Jersey Medical School, Newark, New Jersey, USA; Department of Surgery, Morristown Medical Center, Morristown, New Jersey, USA; Department of Pneumology, Freiburg University Medical Center, Albert-Ludwigs-University, Freiburg, Germany; Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy; Department of Medical Chemistry, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary; and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA haskoge@njms.rutgers.edu.
authors.forename: György
authors.initials: G
authors.lastname: Haskó
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000235:genetics / Q000276:immunology*; D019264:Adoptive Transfer; D000818:Animals; D001419:Bacteria / Q000276:immunology; D058847:Inflammasomes / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D058486:Receptors, Purinergic P2X7 / Q000235:genetics / Q000276:immunology*; D018805:Sepsis / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*
chemical_list: D058847:Inflammasomes; D058486:Receptors, Purinergic P2X7; D000255:Adenosine Triphosphate
keywords: connexin; inflammasome; inflammation; pannexin; phagocytosis