Generation of complement component C5a by ischemic neurons promotes neuronal apoptosis
Generation of complement component C5a by ischemic neurons promotes neuronal apoptosis
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DOI：
10.1096/fj.11-202382
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发表时间：
2012-09-01
期刊：
影响因子：
4.8
通讯作者：
Woodruff, Trent M.
中科院分区：
文献类型：
--
作者：
Pavlovski, Dale;Thundyil, John;Woodruff, Trent M.
C5 a受体存在于中枢神经系统（CNS）的神经元和神经胶质细胞上。然而，激活这些受体的C5 a的起源尚不清楚。在本研究中，我们表明，原代培养的小鼠皮层神经元组成型表达C5，C5 a的前体，并表达经典的受体C5 a，CD 88。与12小时的葡萄糖剥夺，或氧-葡萄糖剥夺（OGD）引起的细胞缺血，神经元表现出增加的凋亡，上调的CD 88，并增加C5 a在媒体的水平。将外源性鼠C5 a（100 nM）加入到神经元培养物中导致细胞凋亡，而不影响细胞坏死。用特异性CD 88受体拮抗剂PMX 53（100 nM）预处理细胞可显著阻断缺血诱导的细胞凋亡（接近50%），CD 88（-/-）小鼠的神经元也受到类似的保护。在小鼠中风模型中，使用大脑中动脉闭塞（MCAO），我们发现大脑中的C5 a水平增加;这也发生在暴露于OGD的大脑切片培养物中。经历MCAO的CD 88（-/-）小鼠具有显著减少的梗死体积和改善的神经评分。总之，我们的结果表明，中枢神经系统中的神经元有能力在缺血应激后产生C5 a，这有可能激活它们的C5 a受体，产生有害的后果。Pavlovski，D.，Thundyil，J.，Monk，P.N.，韦塞尔河一、Taylor，S. M.，伍德拉夫，T. M.缺血神经元产生补体成分C5 a促进神经元凋亡。FASEB J.26，3680-3690（2012）. www.fasebj.org
C5a receptors are found in the central nervous system (CNS), on both neurons and glia. However, the origin of the C5a, which activates these receptors, is unclear. In the present study, we show that primary cultured mouse cortical neurons constitutively express C5, the precursor of C5a, and express the classical receptor for C5a, CD88. With cell ischemia caused by 12 h glucose deprivation, or oxygen-glucose deprivation (OGD), neurons demonstrated increased apoptosis, up-regulation of CD88, and increased levels of C5a in the media. Exogenous murine C5a (100 nM) added to the neuronal cultures resulted in apoptosis, without affecting cell necrosis. Pretreatment of the cells with the specific CD88 receptor antagonist PMX53 (100 nM) significantly blocked ischemia-induced apoptosis (similar to 50%), and neurons from CD88(-/-) mice were similarly protected. In a murine model of stroke, using middle cerebral artery occlusion (MCAO), we found that C5a levels in the brain increased; this also occurred in cerebral slice cultures exposed to OGD. CD88(-/-) mice subjected to MCAO had significantly reduced infarct volumes and improved neurological scores. Taken together, our results demonstrate that neurons in the CNS have the capability to generate C5a following ischemic stress, and this has the potential to activate their C5a receptors, with deleterious consequences.-Pavlovski, D., Thundyil, J., Monk, P. N., Wetsel, R. A., Taylor, S. M., Woodruff, T. M. Generation of complement component C5a by ischemic neurons promotes neuronal apoptosis. FASEB J. 26, 3680-3690 (2012). www.fasebj.org