MAC1 mediates LPS-induced production of superoxide by microglia: The role of pattern recognition receptors in dopaminergic neurotoxicity
MAC1 mediates LPS-induced production of superoxide by microglia: The role of pattern recognition receptors in dopaminergic neurotoxicity
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DOI：
10.1002/glia.20545
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发表时间：
2007-10-01
期刊：
影响因子：
6.2
通讯作者：
Block, Michelle L.
中科院分区：
文献类型：
--
作者：
Pei, Zhong;Pang, Hao;Block, Michelle L.
小胶质细胞源性超氧化物对于炎症诱导的多巴胺能（DA）神经元的选择性丧失至关重要，但小胶质细胞激活的潜在机制仍然不清楚。使用神经胶质细胞和小胶质细胞丰富的文化，从缺乏在MAC 1受体（MAC 1（-/-））的小鼠，我们证明，脂多糖（LPS）治疗的结果在较低的TNF α反应，衰减的DA神经元的损失，并在MAC 1（-/-）文化的细胞外超氧化物的产生。小胶质细胞积累荧光标记的LPS在与质膜，细胞内囊泡，和高尔基体的点状隔间。细胞松弛素D（CD），一种吞噬抑制剂，阻断LPS内化。然而，与对照组相比，来自Toll样受体4缺陷小鼠和MAC 1（-/-）小鼠的小胶质细胞未能显示标记的LPS的细胞内积累的显著减少。用清道夫受体抑制剂岩藻依聚糖预处理，抑制了79%的LPS在小胶质细胞中的积累，而不影响超氧化物，表明LPS内化和超氧化物的产生是由单独的吞噬受体介导的。总之，这些数据表明，MAC 1是必不可少的LPS诱导的超氧化物从小胶质细胞，暗示MAC 1作为一个关键的触发小胶质细胞衍生的氧化应激在炎症介导的神经变性。(c)2007 Wiley-Liss，Inc.
Microglia-derived superoxide is critical for the inflammation-induced selective loss of dopaminergic (DA) neurons, but the underlying mechanisms of microglial activation remain poorly defined. Using neuron-glia and microglia-enriched cultures from mice deficient in the MAC1 receptor (MAC1(-/-)), we demonstrate that lipopolysaccharide (LPS) treatment results in lower TNF alpha response, attenuated loss of DA neurons, and absence of extracellular superoxide production in MAC1(-/-) cultures. Microglia accumulated fluorescently labeled LPS in punctate compartments associated with the plasma membrane, intracellular vesicles, and the Golgi apparatus. Cytochalasin D (CD), an inhibitor of phagocytosis, blocked LPS internalization. However, Microglia derived from Toll-like receptor 4 deficient mice and MAC1(-/-) mice failed to show a significant decrease in intracellular accumulation of labeled LPS, when compared with controls. Pretreatment with the scavenger receptor inhibitor, fucoidan, inhibited 79% of LPS accumulation in microglia without affecting superoxide, indicating that LPS internalization and superoxide production are mediated by separate phagocytosis receptors. Together, these data demonstrate that MAC1 is essential for LPS-induced superoxide from microglia, implicating MAC1 as a critical trigger of microglial-derived oxidative stress during inflammation-mediated neurodegeneration. (c) 2007 Wiley-Liss, Inc.