Differential effects of albumin on microglia and macrophages; implications for neurodegeneration following blood-brain barrier damage
Differential effects of albumin on microglia and macrophages; implications for neurodegeneration following blood-brain barrier damage
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DOI：
10.1111/j.1471-4159.2009.05953.x
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发表时间：
2009-05-01
影响因子：
4.7
通讯作者：
Pocock, Jennifer M.
中科院分区：
文献类型：
--
作者：
Hooper, Claudie;Pinteaux-Jones, Fleur;Pocock, Jennifer M.
血脑屏障损伤后由血源性因子引起的小胶质细胞活化可能在随后的几种神经退行性疾病的神经发病机制中发挥重要作用。暴露的原代培养的大鼠脑小胶质细胞纯，脂肪酸和脂质缺乏大鼠血清白蛋白或馏分V，（脂肪酸和脂质含有大鼠血清白蛋白），引起诱导型一氧化氮合酶（iNOS）的表达，谷氨酸释放，肿瘤坏死因子α（TNF α）和转化生长因子β 1释放。iNOS的表达减弱MAPK/细胞外信号调节激酶通路抑制剂U 0126和磷酸化形式的细胞外信号调节激酶1和2可检测到在小胶质细胞处理与白蛋白或馏分V.谷氨酸释放防止1-α-氨基己二酸和谷胱甘肽水平的小胶质细胞上升暴露于白蛋白。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，脂多糖诱导两种细胞类型中白细胞介素-1 β和肿瘤坏死因子α释放、环氧合酶-2和iNOS表达，表明巨噬细胞中白蛋白的离散脱敏途径在小胶质细胞中不脱敏。因此，脑中的小胶质细胞暴露于白蛋白可能导致血脑屏障破坏后的神经元损伤，并指出驻留的小胶质细胞而不是浸润的巨噬细胞作为治疗靶点。
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 (TNF alpha) 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.