The sympathetic nerve--an integrative interface between two supersystems: the brain and the immune system.
The sympathetic nerve--an integrative interface between two supersystems: the brain and the immune system.
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发表时间：
2000-12
影响因子：
21.1
通讯作者：
I. Elenkov;R. Wilder;G. Chrousos;E. Vizi
中科院分区：
文献类型：
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作者：
I. Elenkov;R. Wilder;G. Chrousos;E. Vizi
大脑和免疫系统是人体的两个主要适应系统。在免疫反应过程中，大脑和免疫系统相互“对话”，这一过程对维持体内平衡至关重要。这种串扰涉及两个主要的通路系统：下丘脑-垂体-肾上腺(HPA)轴和交感神经系统(SNS)。这篇综述集中在SNS在神经免疫相互作用中的作用，这一领域比HPA轴的作用受到的关注要少得多。过去20年积累的证据表明，去甲肾上腺素(NE)符合淋巴器官神经递质/神经调节剂的标准。因此，初级和次级淋巴器官接受广泛的交感神经/去甲肾上腺素能神经支配。在刺激下，NE从这些器官的交感神经末梢释放出来，靶免疫细胞表达肾上腺素受体。通过刺激这些受体，局部释放的NE或循环中的儿茶酚胺，如肾上腺素，影响淋巴细胞的运输、循环和增殖，并调节细胞因子的产生和不同淋巴细胞的功能活动。虽然在骨髓中存在大量的交感神经，特别是在胸腺和粘膜组织中，但我们对交感神经输入对造血、胸腺细胞发育和粘膜免疫的影响的了解非常有限。此外，最近的证据表明，NE和肾上腺素通过刺激β(2)-肾上腺素受体-cAMP-蛋白激酶A通路，抑制抗原提呈细胞和辅助性T细胞(Th)1细胞产生1型/前炎症细胞因子，如IL-12、肿瘤坏死因子-α和干扰素-γ，而刺激产生2型/抗炎细胞因子，如IL-10和转化生长因子-β。通过这一机制，内源性儿茶酚胺可能导致Th1反应和细胞免疫的选择性抑制，并使Th2向体液免疫的优势转变。另一方面，在某些局部反应中，在某些条件下，儿茶酚胺实际上可以通过诱导IL-1、肿瘤坏死因子-α和主要是IL-8的产生来增强局部免疫反应。因此，在免疫反应中激活SNS可能旨在通过诱导中性粒细胞聚集和刺激更特异的体液免疫反应来定位炎症反应，尽管从系统上讲它可以抑制Th1反应，从而保护机体免受促炎细胞因子和其他激活的巨噬细胞产物的不利影响。还讨论了儿茶酚胺的上述免疫调节作用和SNS在某些感染、重大损伤和败血症、自身免疫、慢性疼痛和疲劳综合征以及肿瘤生长中的临床意义。最后，对交感免疫界面的药理学操作进行了综述，重点介绍了在自身免疫性疾病、纤维肌痛和慢性疲劳综合征的实验模型中使用选择性α(2)和β(2)肾上腺素受体激动剂以及磷酸二酯酶IV型拮抗剂和抑制剂的新治疗策略。
The brain and the immune system are the two major adaptive systems of the body. During an immune response the brain and the immune system "talk to each other" and this process is essential for maintaining homeostasis. Two major pathway systems are involved in this cross-talk: the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS). This overview focuses on the role of SNS in neuroimmune interactions, an area that has received much less attention than the role of HPA axis. Evidence accumulated over the last 20 years suggests that norepinephrine (NE) fulfills the criteria for neurotransmitter/neuromodulator in lymphoid organs. Thus, primary and secondary lymphoid organs receive extensive sympathetic/noradrenergic innervation. Under stimulation, NE is released from the sympathetic nerve terminals in these organs, and the target immune cells express adrenoreceptors. Through stimulation of these receptors, locally released NE, or circulating catecholamines such as epinephrine, affect lymphocyte traffic, circulation, and proliferation, and modulate cytokine production and the functional activity of different lymphoid cells. Although there exists substantial sympathetic innervation in the bone marrow, and particularly in the thymus and mucosal tissues, our knowledge about the effect of the sympathetic neural input on hematopoiesis, thymocyte development, and mucosal immunity is extremely modest. In addition, recent evidence is discussed that NE and epinephrine, through stimulation of the beta(2)-adrenoreceptor-cAMP-protein kinase A pathway, inhibit the production of type 1/proinflammatory cytokines, such as interleukin (IL-12), tumor necrosis factor-alpha, and interferon-gamma by antigen-presenting cells and T helper (Th) 1 cells, whereas they stimulate the production of type 2/anti-inflammatory cytokines such as IL-10 and transforming growth factor-beta. Through this mechanism, systemically, endogenous catecholamines may cause a selective suppression of Th1 responses and cellular immunity, and a Th2 shift toward dominance of humoral immunity. On the other hand, in certain local responses, and under certain conditions, catecholamines may actually boost regional immune responses, through induction of IL-1, tumor necrosis factor-alpha, and primarily IL-8 production. Thus, the activation of SNS during an immune response might be aimed to localize the inflammatory response, through induction of neutrophil accumulation and stimulation of more specific humoral immune responses, although systemically it may suppress Th1 responses, and, thus protect the organism from the detrimental effects of proinflammatory cytokines and other products of activated macrophages. The above-mentioned immunomodulatory effects of catecholamines and the role of SNS are also discussed in the context of their clinical implication in certain infections, major injury and sepsis, autoimmunity, chronic pain and fatigue syndromes, and tumor growth. Finally, the pharmacological manipulation of the sympathetic-immune interface is reviewed with focus on new therapeutic strategies using selective alpha(2)- and beta(2)-adrenoreceptor agonists and antagonists and inhibitors of phosphodiesterase type IV in the treatment of experimental models of autoimmune diseases, fibromyalgia, and chronic fatigue syndrome.