Self-regulation of inflammatory cell trafficking in mice by the leukocyte surface apyrase CD39
Self-regulation of inflammatory cell trafficking in mice by the leukocyte surface apyrase CD39
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DOI：
10.1172/jci36433
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发表时间：
2009-05-01
影响因子：
15.9
通讯作者：
Pinsky, David J.
中科院分区：
文献类型：
--
作者：
Hyman, Matthew C.;Petrovic-Djergovic, Danica;Pinsky, David J.
脑缺血部位的白细胞和血小板聚集加剧了脑损伤。内皮细胞质膜上的胞外酶CD39代谢ADP以抑制缺血脑中的血小板聚集。然而，在这种情况下，白细胞表面CD39在调节单核细胞和中性粒细胞运输中的作用尚不清楚。在这里，我们在小鼠身上展示了一种我们认为是一种新的机制，即单核细胞和中性粒细胞上的CD39通过分解受损细胞释放的核苷酸来调节它们自身对缺血脑组织的隔离，从而抑制它们的趋化、黏附和迁移。骨髓重建和提供apyrase，一种水解三磷酸和二磷酸核苷的酶，每一种都使CD39缺陷小鼠的缺血性白血球和脑梗塞正常化。从CD39(-/-)小鼠中提纯的白细胞磷酸化水解腺嘌呤核苷酸和调节血小板反应性的能力明显减弱，这表明白细胞胞外核糖核酸酶调节周围血管核苷酸环境。CD39消散ATP可减少P2X(7)受体的刺激，从而抑制基础白细胞α(M)β(2)整合素的表达。由于α(M)β(2)-整合素阻断逆转了CD39(-/-)小鼠的缺血后炎症表型，这些数据表明，白细胞表面的磷酸水解性活性抑制了本来会促进血栓形成或炎症的细胞-细胞相互作用。这些研究表明，内皮细胞和白细胞上的CD39减少了炎性细胞的运输和血小板的反应性，从而减少了脑缺血后的组织损伤。
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 P2X(7) receptor stimulation and thereby suppressed baseline leukocyte alpha(M)beta(2)-integrin expression. As alpha(M)beta(2)-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.