每个人都曾经历过感染引起的典型症状:发热、精神萎靡以及缺乏食欲.作为大脑对细胞因子—免疫系统的信号分子—做出反应的结果,这些症状都是由大脑精密安排的.但这些细胞因子是如何逾越几乎不可渗透的血脑屏障的,却一直是学术界争论的焦点.
    来自索尔克生物学研究所的最新研究显示,由于刺激因子的性质不同,排列于血脑屏障的局部巨噬细胞在免疫信号进入脑组织的过程中起着完全相反的作用.
    “在启动大脑进入应付感染入侵程序的过程中,巨噬细胞起着加速器的作用,但必要时也可以如突然刹车一样阻止中央炎症反应的发展以避免反应过度.” Jordi Serrats博士如此解释,这位博士后研究员与Jennifer C. Schiltz博士共同领到了这个研究项目,后者曾经是索尔克神经元结构和功能实验室的博士后研究员,现在是位于美国马里兰州贝塞斯达市的统一服务大学(Uniformed Services University)的助理教授.
    索尔克生物学研究所的最新发现发表在2010年1月14日的神经元杂志(the journal Neuron)上,这项发现可能为慢性神经退化性疾病的治疗提供全新的思路,包括肌萎缩性脊髓侧索硬化症、帕金森症、阿尔茨海默病和朊病毒病等,在这些疾病中中心炎症反应机制起着非常重要的作用.
    “在脑组织中被发现的这种潜在的抗炎机制为一系列携带炎症反应组件的中央神经系统疾病的干预治疗提供了新的靶标.” Paul E. Sawchenko博士说,他是这个研究的第一作者,也是神经元结构和功能实验室的教授.
    一旦受到感染,在感染部位会产生炎症因子,如IL-1等.这些因子随血液循环流遍全身并作用于脑组织的神经元细胞,并启动完整的大脑压力反应机制—“下丘脑-垂体-肾上腺轴”(HPA axis)反应.该反应包括下丘脑、正好位于下丘脑下方的脑垂体与肾脏上方的肾上腺的相互作用.
    下丘脑如中央司令部一样发出释放促肾上腺皮质素的命令,随后脑垂体分泌该激素,后者刺激肾上腺大量产生糖皮质激素,从而积蓄能量以应付感染入侵.但糖皮质激素也可以作为免疫抑制剂以阻止细胞因子的过量产生和免疫细胞的过度增殖.
    “细胞因子的分子量较大,难以自由通过血脑屏障,” Sawchenko说,“问题是这些因子如何进入脑组织并引发一系列的适应性反应,如发热、精神不振、嗜睡等,同时激活大脑的压力反应机制,这是在神经免疫学领域困扰人们多年的难题之一.”
    Sawchenko等人在更早的研究发现中认为存在这样一个信号通路:细胞因子作用于血管壁并产生第二信号,后者启动脑组织中的信号通路.紧密排列的血管内皮细胞—脑中所有由这些细胞组成的毛细血管的总长度将近400英里—可以很好的记录循环系统的免疫信号,但这个信号需要非常强才能将其激活.另一方面,对信号更为敏感的外周巨噬细胞却没有直接接触血液.
    为了解这两种细胞在这个过程中的确切作用,Serrats充分利用巨噬细胞可以吞噬并消化固体颗粒的特性,将内含氯屈膦酸钠—一种可致细胞死亡的药物—的脂质体植入实验动物的侧脑室,吞噬这些脂质体的的巨噬细胞将被选择性杀死.
    缺少外周巨噬细胞的实验动物无法对血液中产生的IL-1做出反应并启动大脑的急性期反应,而这有助于身体对抗感染并引起熟悉的“患病”感觉.但出乎意料的是,索尔克生物学研究所却发现巨噬细胞可以抑制血管内皮细胞的促炎活性,这些血管的构成细胞只有在接触脂多糖—革兰氏阴性菌细胞壁的主要成分—的时候才会作出反应,当然,这种反应是相当强烈的.
    “许多神经退化性疾病因全身性感染或炎症反应而恶化,” Sawchenko说,“一旦我们能够找到介导外周巨噬细胞和血管内皮细胞间双向信号传导的分子,就可以开发一种新策略,以应对由中心炎症反应引起的对健康不利的后果.”


Dual role for immune cells in the brain
    We all have at one time or another experienced the typical signs of an infection: the fever, the listlessness, the lack of appetite. They are orchestrated by the brain in response to circulating cytokines, the signaling molecules of the immune system. But just how cytokines\' reach extends beyond the almost impenetrable blood-brain barrier has been the topic of much dispute.
    In their latest study, researchers at the Salk Institute for Biological Studies describe how, depending on the nature of the stimulus, resident macrophages lined up along the blood-brain barrier play opposing roles in the transmission of immune signals into the brain.
    "These macrophages act as accelerators to enlist the brain\'s participation in dealing with immune insults, but when necessary slam on the brakes to prevent the central inflammatory response from going overboard," explains postdoctoral researcher Jordi Serrats, Ph.D., who co-led the study with Jennifer C. Schiltz, Ph.D., formerly a postdoctoral researcher in the Salk\'s Neuronal Structure and Function Laboratory and now an assistant professor at the Uniformed Services University in Bethesda, Maryland.
    The Salk researchers\' findings, which are published in the Jan. 14, 2010 edition of the journal Neuron, may pave the way for novel therapies for sufferers of chronic neurodegenerative diseases, such as Amyotrophic Lateral Sclerosis (ALS), Parkinson\'s, Alzheimer\'s and prion diseases, in which central inflammatory mechanisms play an important role.
    "The fact that we have identified a potent anti-inflammatory mechanism in the brain presents a new target to intervene in the wide range of central nervous system diseases that possess an inflammatory component," says the study\'s senior author, Paul E. Sawchenko, Ph.D., a professor in the Neuronal Structure and Function Laboratory.
    In response to an infection, inflammatory cytokines such as interleukin-1 are generated at the site of infection. These cytokines circulate in the blood and communicate with neurons in the brain to engage the hypothalamo-pituitary-adrenal (HPA) axis, an integral part of the brain\'s stress response machinery. The HPA axis involves the interaction of the hypothalamus, the pituitary gland, which sits just below the hypothalamus and the adrenal glands at the top of the kidneys.
    Like a central command center, the hypothalamus sends out corticotropin-releasing factor, which stimulates the pituitary gland to secrete adrenocorticotropic hormone. The latter signals the adrenal glands to ramp up the production of glucocorticoids, which mobilize energy reserves to cope with inflammatory insults. But they also act as very powerful immunosuppressants preventing excessive cytokine production and immune cell proliferation.


    "Cytokines are big molecules that don\'t cross the blood-brain barrier freely," says Sawchenko. "The question of how these molecules access the brain to trigger this whole array of adaptive responses such as fever, inactivity, sleepiness, and activation of the brain\'s stress response machinery has been a nagging problem in the side of neuroimmunology for many years."
    Earlier research by Sawchenko and others suggested a vascular route whereby cytokines interact with vessel walls to generate secondary messengers, which then engage the relevant circuitry in the brain. Tightly packed endothelial cells, which line almost 400 miles of narrow capillaries throughout the brain, are perfectly positioned to record circulating immune signals but they require a very strong signal to become activated. Perivascular macrophages, on the other hand, are more sensitive but don\'t have direct access to the bloodstream.
    To disentangle the exact role of these two cell types, Serrats took advantage of the macrophages\' ability to engulf and ingest solid particles. He injected liposomes containing clodronate, a drug that can cause cell death, into the lateral cerebral ventricle. The liposomes were taken up by the macrophages, which were selectively killed off.
    Without perivascular macrophages, the animals were unable to respond to blood-borne interleukin-1 and initiate the brain\'s so-called acute phase responses, which help the body deal with the challenge at hand but also cause the familiar feeling of "being sick." But to their surprise, the Salk researchers found that the same cells put a damper on the pro-inflammatory activities of endothelial cells, which form the lining of blood vessels and are only stirred to action-but very powerfully once they are-when they encounter lipopolysaccharide, a key component of the cell wall of certain bacteria.
    "Many neurodegenerative diseases are worsened by systemic inflammation or infections," says Sawchenko. "Once we identify the molecules that mediate the two-way communication between perivascular macrophages and endothelial cells we can develop strategies for managing the adverse health consequences of central inflammatory responses."

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