PP2 and piceatannol inhibit PrP106-126-induced iNOS activation mediated by CD36 in BV2 microglia.
PP2 and piceatannol inhibit PrP106-126-induced iNOS activation mediated by CD36 in BV2 microglia.
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DOI：
10.1093/abbs/gmt074
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发表时间：
2013-09
影响因子：
3.7
通讯作者：
Siming Zhang;Lifeng Yang;M. Kouadir;Rongrong Tan;Yun Lu;Jiaxin Chang;Binrui Xu;Xiaomin Yin;Xiangmei Zhou;Deming Zhao
中科院分区：
文献类型：
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作者：
Siming Zhang;Lifeng Yang;M. Kouadir;Rongrong Tan;Yun Lu;Jiaxin Chang;Binrui Xu;Xiaomin Yin;Xiangmei Zhou;Deming Zhao
朊病毒疾病是一组人类和动物的传染性致死性神经退行性疾病，包括牛海绵状脑病、痒病和克雅氏病。小胶质细胞是中枢神经系统的巨噬细胞，对病理组织改变非常敏感，改变其形态和表型，以采取所谓的激活状态，并在病理生理脑损伤中发挥免疫功能。尽管最近的研究结果为小胶质细胞在朊病毒中观察到的促炎事件中所起的作用提供了有价值的见解，但负责启动这些反应的细胞内信号分子仍有待阐明。小胶质细胞的激活似乎涉及PrP106-126结合和细胞表面免疫和粘附分子（如CD36和整合素）的激活，随后募集Src家族酪氨酸激酶（如Fyn、Lyn和Syk激酶）。在本研究中，我们发现CD36参与了prp106 -126诱导的小胶质细胞激活，PP2和picatan醇（Pic）可以消除神经毒性朊病毒多肽诱导的小胶质细胞诱导的一氧化氮合酶激活。这些发现揭示了PP2和Pic作为Src家族激酶Fyn和酪氨酸激酶Syk抑制剂参与神经毒性朊蛋白肽-小胶质细胞相互作用的先前未被认识的作用，从而为神经毒性朊蛋白肽激活小胶质细胞的机制提供了新的见解。
Prion diseases are a group of transmissible fatal neurodegenerative disorders of humans and animals, including bovine spongiform encephalopathy, scrapie, and Creutzfeldt-Jakob disease. Microglia, the resident macrophages of the central nervous system, are exquisitely sensitive to pathological tissue alterations, altering their morphology and phenotype to adopt a so-called activated state and perform immunological functions in response to pathophysiological brain insults. Although recent findings have provided valuable insights into the role microglia play in the proinflammatory events observed in prion, the intracellular signaling molecules responsible for the initiation of these responses remain to be elucidated. It seems that microglial activation involve PrP106-126 binding and the activation of cell surface immune and adhesion molecules such as CD36 and integrins, with the subsequent recruitment of Src family tyrosine kinases such as Fyn, Lyn, and Syk kinases. In the present study, we show that CD36 is involved in PrP106-126-induced microglial activation and that PP2 and piceatannol (Pic) can abrogate neurotoxic prion peptides-induced inducible nitric oxide synthase activation in microglia. These findings unveil a previously unrecognized role of PP2 and Pic as Src family kinase Fyn and the tyrosine kinase Syk inhibitor involved in neurotoxic prion peptides-microglia interactions, thus providing new insights into mechanisms underlying the activation of microglia by neurotoxic prion peptides.