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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >C3-dependent mechanism of microglial priming relevant to multiple sclerosis
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C3-dependent mechanism of microglial priming relevant to multiple sclerosis

机译：C3依赖的小胶质细胞引发与多发性硬化症相关的机制

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摘要

Microglial priming predisposes the brain to neurodegeneration and affects disease progression. The signal to switch from the quiescent to the primed state is unknown. We show that deleting the C3 con-vertase regulator complement receptor 1-related protein y (Crry) induces microglial priming. Mice that were double-knockout for Crry and either C3 or factor B did not show priming, demonstrating dependence on alternative pathway activation. Colocalization of C3b/ iC3b and CR3 implicated the CR3/iC3b interaction in priming. Systemic lipopolysaccharide challenge overactivated primed microglia with florid expression of proinf lammatory molecules, which were blocked by complement inhibition. Relevance for neurodegenerative disease is exemplified by human multiple sclerosis (MS) and by experimental autoimmune encephalomyelitis (EAE), a model of MS. In human MS, microglial priming was evident in perilesional white matter, in close proximity to C3b/iC3b deposits. EAE was accelerated and exacerbated in Crry-def icient mice, and was dependent on C activation. In summary, C3-dependent microglial priming confers susceptibility to other challenges. Our observations are relevant to progression in MS and other neurological diseases exacerbated by acute insults.
机译：小胶质启动使大脑容易发生神经变性并影响疾病的进展。从静态切换到准备状态的信号是未知的。我们显示删除C3转换酶调节剂补体受体1相关蛋白y（Crry）诱导小胶质启动。对Crry和C3或B因子双重敲除的小鼠未显示致敏性，表明对替代途径激活的依赖性。 C3b / iC3b和CR3的共定位暗示了CR3 / iC3b在启动过程中的相互作用。全身性脂多糖攻击过活化的初生小胶质细胞，其前激进分子的花状表达被补体抑制所阻断。神经退行性疾病的相关性可以通过人类多发性硬化症（MS）和实验性自身免疫性脑脊髓炎（EAE）（一种MS模型）来举例说明。在人类MS中，在靠近C3b / iC3b沉积物的病灶周围白质中明显存在小胶质细胞引发。 EAE在缺乏Crry的小鼠中被加速和加剧，并依赖于C的激活。总之，依赖C3的小胶质细胞引发赋予其他挑战易感性。我们的观察结果与急性损伤加重的MS和其他神经系统疾病的进展有关。

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    Valeria Ramaglia; Timothy R. Hughes; Rossen M. Donev; Marieta M. Ruseva; Xiaobo Wu; Inge Huitinga; Frank Baas; James W. Neal; B. Paul Morgan;

  • 作者单位

    Departments of Infection, Immunity, and Biochemistry and Cardiff University, Cardiff CF14 4XN, United Kingdom;

    Departments of Infection, Immunity, and Biochemistry and Cardiff University, Cardiff CF14 4XN, United Kingdom;

    Departments of Infection, Immunity, and Biochemistry and Cardiff University, Cardiff CF14 4XN, United Kingdom;

    Departments of Infection, Immunity, and Biochemistry and Cardiff University, Cardiff CF14 4XN, United Kingdom;

    Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110;

    Department of Neuroimmunology, Netherlands Institute for Neuroscience, 1105 AZ Amsterdam, The Netherlands;

    Department of Genome Analysis, Academic Medical Center, 1105 AZ Amsterdam,The Netherlands;

    Pathology, School of Medicine, Cardiff University, Cardiff CF14 4XN, United Kingdom;

    Departments of Infection, Immunity, and Biochemistry and Cardiff University, Cardiff CF14 4XN, United Kingdom;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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