Proinflammatory tachykinins that signal through the neurokinin 1 receptor promote survival of dendritic cells and potent cellular immunity
Proinflammatory tachykinins that signal through the neurokinin 1 receptor promote survival of dendritic cells and potent cellular immunity
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DOI：
10.1182/blood-2008-06-163121
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发表时间：
2009-03-26
期刊：
影响因子：
20.3
通讯作者：
Larregina, Adriana T.
中科院分区：
文献类型：
--
作者：
Janelsins, Brian M.;Mathers, Alicia R.;Larregina, Adriana T.
树突状细胞(DC)是以刺激细胞免疫反应为主的免疫治疗方案的首选靶点。然而，不管最初的有希望的结果如何，体外产生的DC并不总是促进免疫刺激反应。DC依赖免疫的结果受促炎细胞因子和神经肽的调节。速激肽家族的促炎性神经肽，包括P物质(SP)和血激素-1(HK-1)，与神经激肽1受体(NK1R)结合，促进刺激性免疫反应。然而，促炎症速激肽影响DC免疫功能的能力仍然难以捉摸。在本工作中，我们证明了在粒细胞巨噬细胞集落刺激因子(GM-CSF)和白介素4(IL-4)的存在下，小鼠骨髓来源的DC(BMDCs)表达功能性的NK1R。通过NK1R与SP、HK-1或合成激动剂[Sar(9)Met(O-2)(11)]-SP一起传递信号，可使DC免于因缺乏GM-CSF和IL-4而诱导的凋亡。机制分析表明，NK1R激动型结合通过PI3K-Akt信号通路促进DC存活。在过继转移实验中，NK1R信号的载银BMDCs在引流淋巴结中表现出更长的寿命，从而增强和延长了效应者的细胞免疫。我们的结果有助于理解控制DC功能的免疫和神经系统之间的相互作用，并为体外产生强大的免疫刺激DC提供了一种新的方法。(血。2009；113：3017-3026)
Dendritic cells (DCs) are the preferred targets for immunotherapy protocols focused on stimulation of cellular immune responses. However, regardless of initial promising results, ex vivo-generated DCs do not always promote immune-stimulatory responses. The outcome of DC-dependent immunity is regulated by proinflammatory cytokines and neuropeptides. Proinflammatory neuropeptides of the tachykinin family, including substance P (SP) and hemokinin-1 (HK-1), bind the neurokinin 1 receptor (NK1R) and promote stimulatory immune responses. Nevertheless, the ability of pro-inflammatory tachykinins to affect the immune functions of DCs remains elusive. In the present work, we demonstrate that mouse bone marrow-derived DCs (BMDCs) generated in the presence of granulocyte macrophage-colony stimulating factor (GM-CSF) and interleukin-4 (IL-4), express functional NK1R. Signaling via NK1R with SP, HK-1, or the synthetic agonist [Sar(9)Met(O-2)(11)]-SP rescues DCs from apoptosis induced by deprivation of GM-CSF and IL-4. Mechanistic analysis demonstrates that NK1R agonistic binding promotes DC survival via PI3K-Akt signaling cascade. In adoptive transfer experiments, NK1R-signaled BMDCs loaded with Ag exhibit increased longevity in draining lymph nodes, resulting in enhanced and prolonged effector cellular immunity. Our results contribute to the understanding of the interactions between the immune and nervous systems that control DC function and present a novel approach for ex vivo generation of potent immune-stimulatory DCs. (Blood. 2009; 113: 3017-3026)