Acid sphingomyelinase activity triggers microparticle release from glial cells.
Acid sphingomyelinase activity triggers microparticle release from glial cells.
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DOI：
10.1038/emboj.2009.45
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发表时间：
2009-04-22
期刊：
影响因子：
11.4
通讯作者：
Verderio, Claudia
中科院分区：
文献类型：
--
作者：
Bianco, Fabio;Perrotta, Cristiana;Novellino, Luisa;Francolini, Maura;Riganti, Loredana;Menna, Elisabetta;Saglietti, Laura;Schuchman, Edward H.;Furlan, Roberto;Clementi, Emilio;Matteoli, Michela;Verderio, Claudia
我们先前已经表明，小胶质细胞，中枢神经系统的免疫细胞，释放微粒从细胞质膜后ATP刺激。这些囊泡含有并释放IL-1β，IL-1β是CNS炎症事件中的关键细胞因子。在这项研究中，我们发现微粒也被星形胶质细胞释放，我们深入了解了它们脱落的机制。我们发现，在激活ATP受体P2 X7，微粒脱落与快速激活的酸性鞘磷脂酶，移动到质膜外小叶。ATP诱导的脱落和IL-1β释放通过抑制酸性鞘磷脂酶而显著减少，并且在来自酸性鞘磷脂酶敲除小鼠的神经胶质培养物中被完全阻断。我们还表明p38 MAPK级联与整个过程相关，因为特异性激酶抑制剂强烈降低酸性鞘磷脂酶活化、微粒脱落和IL-1β释放。我们的结果代表了第一次证明酸性鞘磷脂酶的激活对于从胶质细胞释放微粒是必要的和充分的，并且定义了微粒形成和IL-1β释放的关键分子效应物，从而为治疗神经炎性疾病开辟了新的策略。
We have earlier shown that microglia, the immune cells of the CNS, release microparticles from cell plasma membrane after ATP stimulation. These vesicles contain and release IL-1β, a crucial cytokine in CNS inflammatory events. In this study, we show that microparticles are also released by astrocytes and we get insights into the mechanism of their shedding. We show that, on activation of the ATP receptor P2X7, microparticle shedding is associated with rapid activation of acid sphingomyelinase, which moves to plasma membrane outer leaflet. ATP-induced shedding and IL-1β release are markedly reduced by the inhibition of acid sphingomyelinase, and completely blocked in glial cultures from acid sphingomyelinase knockout mice. We also show that p38 MAPK cascade is relevant for the whole process, as specific kinase inhibitors strongly reduce acid sphingomyelinase activation, microparticle shedding and IL-1β release. Our results represent the first demonstration that activation of acid sphingomyelinase is necessary and sufficient for microparticle release from glial cells and define key molecular effectors of microparticle formation and IL-1β release, thus, opening new strategies for the treatment of neuroinflammatory diseases.
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