title: Self-regulation of inflammatory cell trafficking in mice by the leukocyte surface apyrase CD39.
abstract: Leukocyte and platelet accumulation at sites of cerebral ischemia exacerbate cerebral damage. The ectoenzyme CD39 on the plasmalemma of endothelial cells metabolizes ADP to suppress platelet accumulation in the ischemic brain. However, the role of leukocyte surface CD39 in regulating monocyte and neutrophil trafficking in this setting is not known. Here we have demonstrated in mice what we believe to be a novel mechanism by which CD39 on monocytes and neutrophils regulates their own sequestration into ischemic cerebral tissue, by catabolizing nucleotides released by injured cells, thereby inhibiting their chemotaxis, adhesion, and transmigration. Bone marrow reconstitution and provision of an apyrase, an enzyme that hydrolyzes nucleoside tri- and diphosphates, each normalized ischemic leukosequestration and cerebral infarction in CD39-deficient mice. Leukocytes purified from Cd39-/- mice had a markedly diminished capacity to phosphohydrolyze adenine nucleotides and regulate platelet reactivity, suggesting that leukocyte ectoapyrases modulate the ambient vascular nucleotide milieu. Dissipation of ATP by CD39 reduced P2X7 receptor stimulation and thereby suppressed baseline leukocyte alphaMbeta2-integrin expression. As alphaMbeta2-integrin blockade reversed the postischemic, inflammatory phenotype of Cd39-/- mice, these data suggest that phosphohydrolytic activity on the leukocyte surface suppresses cell-cell interactions that would otherwise promote thrombosis or inflammation. These studies indicate that CD39 on both endothelial cells and leukocytes reduces inflammatory cell trafficking and platelet reactivity, with a consequent reduction in tissue injury following cerebral ischemic challenge.
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan Medical Center, Ann Arbor, USA. mchyman@umich.edu
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Hyman
authors.forename: Danica
authors.initials: D
authors.lastname: Petrovic-Djergovic
authors.forename: Scott H
authors.initials: SH
authors.lastname: Visovatti
authors.forename: Hui
authors.initials: H
authors.lastname: Liao
authors.forename: Sunitha
authors.initials: S
authors.lastname: Yanamadala
authors.forename: Diane
authors.initials: D
authors.lastname: Bouïs
authors.forename: Enming J
authors.initials: EJ
authors.lastname: Su
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Lawrence
authors.forename: M Johan
authors.initials: MJ
authors.lastname: Broekman
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Marcus
authors.forename: David J
authors.initials: DJ
authors.lastname: Pinsky
mesh_terms: D015720:5'-Nucleotidase / Q000037:antagonists & inhibitors; D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D015703:Antigens, CD / Q000502:physiology*; D001081:Apyrase / Q000494:pharmacology / Q000502:physiology*; D016026:Bone Marrow Transplantation; D002545:Brain Ischemia / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D042783:Endothelial Cells / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007962:Leukocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D016177:Macrophage-1 Antigen / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism; D015539:Platelet Activation / Q000502:physiology; D058919:Purinergic P2 Receptor Antagonists; D034622:RNA Interference; D018048:Receptors, Purinergic P2 / Q000235:genetics; D018183:Transplantation Chimera / Q000502:physiology
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D004791:Enzyme Inhibitors; D016177:Macrophage-1 Antigen; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D015720:5'-Nucleotidase; D001081:Apyrase; C067869:CD39 antigen