CD38 exacerbates focal cytokine production, postischemic inflammation and brain injury after focal cerebral ischemia.
CD38 exacerbates focal cytokine production, postischemic inflammation and brain injury after focal cerebral ischemia.
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DOI：
10.1371/journal.pone.0019046
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Magnus T
中科院分区：
文献类型：
--
作者：
Choe CU;Lardong K;Gelderblom M;Ludewig P;Leypoldt F;Koch-Nolte F;Gerloff C;Magnus T
越来越多的证据表明，炎症过程显著影响缺血性卒中的脑损伤和临床损害。虽然早期的研究表明淋巴细胞的关键作用，但最近的数据强调了先天免疫的协调功能，即，巨噬细胞和小胶质细胞。双功能受体和胞外酶CD 38合成钙动员第二信使（例如，环ADP-核糖），其已被证明是骨髓免疫细胞的活化和迁移所必需的。因此，我们在脑缺血再灌注小鼠模型中研究了中风中CD 38的动态变化以及CD 38缺乏对细胞因子产生、炎症和脑损伤的影响。我们发现，局灶性脑缺血和再灌注后，与野生型小鼠相比，CD 38缺陷小鼠中趋化因子MCP-1的局部表达减弱。相反，在6小时后，在外周血中未观察到MCP-1表达的显著诱导。流式细胞术分析显示，在CD 38缺陷小鼠的缺血半球中浸润的巨噬细胞和淋巴细胞较少，而驻留的小胶质细胞的数量没有改变。野生型小鼠局灶性脑缺血后，在巨噬细胞和CD 8+细胞中观察到CD 38表达上调，而在小胶质细胞中CD 38表达无变化。最后，我们证明，CD 38-缺陷减少脑缺血性损伤和持续的神经功能缺损，再灌注三天后，在这个小鼠暂时大脑中动脉闭塞（tMCAO）模型。CD 38在脑卒中后受到不同程度的调节，其缺乏会减弱缺血后趋化因子的产生、免疫细胞浸润和暂时性缺血和再灌注后的脑损伤。因此，CD 38可能成为缺血性卒中的治疗靶点。
Converging evidence suggests that inflammatory processes significantly influence brain injury and clinical impairment in ischemic stroke. Although early studies suggested a key role of lymphocytes, recent data has emphasized the orchestrating function of innate immunity, i.e., macrophages and microglia. The bifunctional receptor and ectoenzyme CD38 synthesizes calcium-mobilizing second messengers (e.g., cyclic ADP-ribose), which have been shown to be necessary for activation and migration of myeloid immune cells. Therefore, we investigated the dynamics of CD38 in stroke and the impact of CD38-deficiency on cytokine production, inflammation and cerebral damage in a mouse model of cerebral ischemia-reperfusion. We show that the local expression of the chemokine MCP-1 was attenuated in CD38-deficient mice compared with wildtype mice after focal cerebral ischemia and reperfusion. In contrast, no significant induction of MCP-1 expression was observed in peripheral blood after 6 hours. Flow cytometry analysis revealed less infiltrating macrophages and lymphocytes in the ischemic hemisphere of CD38-deficient mice, whereas the amount of resident microglia was unaltered. An up-regulation of CD38 expression was observed in macrophages and CD8+ cells after focal cerebral ischemia in wildtype mice, whereas CD38 expression was unchanged in microglia. Finally, we demonstrate that CD38-deficiency decreases the cerebral ischemic injury and the persistent neurological deficit after three days of reperfusion in this murine temporary middle cerebral artery occlusion (tMCAO) model. CD38 is differentially regulated following stroke and its deficiency attenuates the postischemic chemokine production, the immune cell infiltration and the cerebral injury after temporary ischemia and reperfusion. Therefore CD38 might prove a therapeutic target in ischemic stroke.
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影响因子：
82.9
作者：
Liesz, Arthur;Suri-Payer, Elisabeth;Veltkamp, Roland
通讯作者：
Veltkamp, Roland
影响因子：
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作者：
Gelderblom, Mathias;Leypoldt, Frank;Magnus, Tim
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Lund, FE
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作者：
Gourmala, NG;Buttini, M;Boddeke, HWGM
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Boddeke, HWGM