Published online before print October 12, 2006, doi: 10.1161/01.RES.0000250174.31269.70
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© 2006 American Heart Association, Inc.
Cellular Biology |
ATP Release From Activated Neutrophils Occurs via Connexin 43 and Modulates Adenosine-Dependent Endothelial Cell Function
From the Department of Anesthesiology and Intensive Care Medicine (H.K.E., T.E., A.M., N.K., C.K., T.W.), Tübingen University Hospital, Germany; Institut für Pathophysiologie (K.B., R.S.), Zentrum für Innere Medizin, Universitätsklinikum Essen, Germany; Transplantation Center (S.C.R.), Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School; and Center for Experimental Therapeutics and Reperfusion Injury (S.P.C.), Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass.
Correspondence to Holger K. Eltzschig, MD, PhD, Department of Anesthesiology and Intensive Care Medicine, Tübingen University Hospital, Waldhörnle Str. 22, D-72072 Tübingen, Germany. E-mail heltzschig{at}partners.org
Extracellular ATP liberated during hypoxia and inflammation can either signal directly on purinergic receptors or can activate adenosine receptors following phosphohydrolysis to adenosine. Given the association of polymorphonuclear leukocytes (PMNs) with adenine-nucleotide/nucleoside signaling in the inflammatory milieu, we hypothesized that PMNs are a source of extracellular ATP. Initial studies using high-performance liquid chromatography and luminometric ATP detection assays revealed that PMNs release ATP through activation-dependent pathways. In vitro models of endothelial barrier function and neutrophil/endothelial adhesion indicated that PMN-derived ATP signals through endothelial adenosine receptors, thereby promoting endothelial barrier function and attenuating PMN/endothelial adhesion. Metabolism of extracellular ATP to adenosine required PMNs, and studies addressing these metabolic steps revealed that PMN express surface ecto-apyrase (CD39). In fact, studies with PMNs derived from cd39–/– mice showed significantly increased levels of extracellular ATP and lack of ATP dissipation from their supernatants. After excluding lytic ATP release, we used pharmacological strategies to reveal a potential mechanism involved in PMN-dependent ATP release (eg, verapamil, dipyridamole, brefeldin A, 18-
-glycyrrhetinic acid, connexin-mimetic peptides). These studies showed that PMN ATP release occurs through connexin 43 (Cx43) hemichannels in a protein/phosphatase-A–dependent manner. Findings in human PMNs were confirmed in PMNs derived from induced Cx43–/– mice, whereby activated PMNs release less than 15% of ATP relative to littermate controls, whereas Cx43 heterozygote PMNs were intermediate in their capacity for ATP release (P<0.01). Taken together, our results identify a previously unappreciated role for Cx43 in activated PMN ATP release, therein contributing to the innate metabolic control of the inflammatory milieu.
Key Words: nucleotide • nucleoside • adenosine • endothelia • inflammation • ATP • connexin • inflammation • hypoxia
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