MAC1 mediates LPS-induced production of superoxide by microglia: The role of pattern recognition receptors in dopaminergic neurotoxicity

被引:74
作者
Pei, Zhong
Pang, Hao
Qian, Li
Yang, Sufen
Wang, Tonggauang
Zhang, Wei
Wu, Xeufei
Dallas, Shannon
Wilson, Belinda
Reece, Jeffrey M.
Miller, David S.
Hong, Jau-Shyong
Block, Michelle L.
机构
[1] NIEHS, Lab Pharmacol & Chem, Neuropharmacol Sect, Res Triangle Pk, NC 27709 USA
[2] Sun Yat Sen Univ, Affiliated Hosp 1, Dept Neurol, Guangzhou 510275, Guangdong, Peoples R China
[3] Univ N Carolina, Comprehens Ctr Inflammatory Disorders, Chapel Hill, NC USA
[4] NIEHS, Confocal Microscopy Ctr, Lab Signal Transduct, Res Triangle Pk, NC 27709 USA
关键词
MAC1; LPS; microglia; dopaminergic neurotoxicity; superoxide; reactive oxygen species; phagocytosis;
D O I
10.1002/glia.20545
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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.
引用
收藏
页码:1362 / 1373
页数:12
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