Hooper Claudie, Pinteaux-Jones Fleur, Fry Victoria A H, Sevastou Ioanna G, Baker David, Heales Simon J, Pocock Jennifer M
Kings College London, MRC Centre for Neurodegeneration Research, Institute of Psychiatry, London, UK.
J Neurochem. 2009 May;109(3):694-705. doi: 10.1111/j.1471-4159.2009.05953.x. Epub 2009 Feb 2.
Microglial activation by blood-borne factors following blood-brain barrier damage may play a significant role in subsequent neuropathogenesis of several neurodegenerative diseases. Exposure of primary cultured rat brain microglia to pure, fatty acid- and lipid-deficient rat serum albumin or fraction V, (fatty acid and lipid-containing rat serum albumin), caused inducible nitric oxide synthase (iNOS) expression, glutamate release, tumour necrosis factor alpha (TNFalpha) and transforming growth factor-beta1 release. iNOS expression was attenuated by the MAPK/extracellular signal-regulated kinase pathway inhibitor U0126 and the phosphorylated forms of extracellular signal-regulated kinase 1 and 2 were detectable in microglia treated with albumin or fraction V. Glutamate release was prevented by l-alpha-aminoadipate and glutathione levels in microglia rose on exposure to albumin. Conditioned medium from microglia exposed to albumin or fraction V was neurotoxic. Peripheral macrophages were resistant to the effects of albumin but both microglia and macrophages responded to lipopolysaccharide, which induced interleukin-1 beta and tumour necrosis factor alpha release, cyclooxygenase-2 and iNOS expression in both cell types, indicating a discrete desensitised pathway in macrophages for albumin which was not desensitised in microglia. Thus, exposure of microglia in the brain to albumin may contribute to neuronal damage following blood-brain barrier breakdown and point to resident microglia rather than infiltrating macrophages as therapeutic targets.
血脑屏障受损后，血源性因子激活小胶质细胞可能在几种神经退行性疾病随后的神经病理发生过程中发挥重要作用。将原代培养的大鼠脑小胶质细胞暴露于纯的、缺乏脂肪酸和脂质的大鼠血清白蛋白或组分V（含脂肪酸和脂质的大鼠血清白蛋白），会导致诱导型一氧化氮合酶（iNOS）表达、谷氨酸释放、肿瘤坏死因子α（TNFα）和转化生长因子β1释放。丝裂原活化蛋白激酶/细胞外信号调节激酶途径抑制剂U0126可减弱iNOS表达，在用白蛋白或组分V处理的小胶质细胞中可检测到细胞外信号调节激酶1和2的磷酸化形式。L-α-氨基己二酸可阻止谷氨酸释放，小胶质细胞暴露于白蛋白时谷胱甘肽水平升高。暴露于白蛋白或组分V的小胶质细胞的条件培养基具有神经毒性。外周巨噬细胞对白蛋白的作用具有抗性，但小胶质细胞和巨噬细胞均对脂多糖有反应，脂多糖可诱导两种细胞类型释放白细胞介素-1β和肿瘤坏死因子α，诱导环氧化酶-2和iNOS表达，表明巨噬细胞中存在一条对白蛋白不敏感的离散途径，而小胶质细胞中不存在这种不敏感途径。因此，脑内小胶质细胞暴露于白蛋白可能导致血脑屏障破坏后神经元损伤，并表明驻留小胶质细胞而非浸润性巨噬细胞是治疗靶点。
