Deficiency of RAMP1 Attenuates Antigen-Induced Airway Hyperresponsiveness in Mice
Deficiency of RAMP1 Attenuates Antigen-Induced Airway Hyperresponsiveness in Mice
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DOI：
10.1371/journal.pone.0102356
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发表时间：
2014-07-10
期刊：
影响因子：
3.7
通讯作者：
Caron, Kathleen M.
中科院分区：
文献类型：
--
作者：
Li, Manyu;Wetzel-Strong, Sarah E.;Caron, Kathleen M.
哮喘是一种影响肺部的慢性炎症性疾病，其特征是在暴露于环境触发因素后发作时呼吸困难。降钙素基因相关肽(CGRP)是一种可能在哮喘发病中起病理作用的神经肽。CGRP受体由两部分组成，包括G蛋白偶联受体、降钙素受体样受体(CLR)和受体活性修饰蛋白1(RAMP1)。RAMP，包括RAMP1，除了帮助受体定位到细胞表面外，还介导配体的特异性。由于关于CGRP在哮喘中的作用一直存在争议，我们试图在哮喘动物模型中确定CGRP信号消融的效果。使用基因打靶技术，我们通过切除外显子3产生了缺乏RAMP1的小鼠。在确定这些小鼠是存活的和明显正常的之后，我们在评估乙酰甲胆碱攻击后的呼吸道阻力和炎症之前，对动物进行了卵白蛋白致敏。我们发现，与野生型动物相比，缺乏RAMP1的小鼠的呼吸道阻力和炎症都有所降低。此外，我们发现，CGRP受体的G蛋白受体成分CLR减少50%，也可以改善过敏性哮喘模型的呼吸道阻力和炎症。有趣的是，平滑肌细胞CLR的丢失并没有改变呼吸道阻力，这表明CGRP不会直接作用于平滑肌细胞来驱动气道高反应性。综上所述，这些数据表明，通过RAMP1和CLR的信号在哮喘病理中起着中介作用。由于RAMP1和CLR相互作用形成CGRP受体，我们的数据表明，可能在肺内皮细胞和炎症细胞上的CGRP信号异常参与了哮喘的病理生理过程。最后，由于RAMP-受体界面在药理上易于处理，因此有可能开发针对RAMP1/CLR界面的化合物来辅助治疗哮喘。
Asthma is a chronic inflammatory disease affecting the lung, characterized by breathing difficulty during an attack following exposure to an environmental trigger. Calcitonin gene-related peptide (CGRP) is a neuropeptide that may have a pathological role in asthma. The CGRP receptor is comprised of two components, which include the G-protein coupled receptor, calcitonin receptor-like receptor (CLR), and receptor activity-modifying protein 1 (RAMP1). RAMPs, including RAMP1, mediate ligand specificity in addition to aiding in the localization of receptors to the cell surface. Since there has been some controversy regarding the effect of CGRP on asthma, we sought to determine the effect of CGRP signaling ablation in an animal model of asthma. Using gene-targeting techniques, we generated mice deficient for RAMP1 by excising exon 3. After determining that these mice are viable and overtly normal, we sensitized the animals to ovalbumin prior to assessing airway resistance and inflammation after methacholine challenge. We found that mice lacking RAMP1 had reduced airway resistance and inflammation compared to wildtype animals. Additionally, we found that a 50% reduction of CLR, the G-protein receptor component of the CGRP receptor, also ameliorated airway resistance and inflammation in this model of allergic asthma. Interestingly, the loss of CLR from the smooth muscle cells did not alter the airway resistance, indicating that CGRP does not act directly on the smooth muscle cells to drive airway hyperresponsiveness. Together, these data indicate that signaling through RAMP1 and CLR plays a role in mediating asthma pathology. Since RAMP1 and CLR interact to form a receptor for CGRP, our data indicate that aberrant CGRP signaling, perhaps on lung endothelial and inflammatory cells, contributes to asthma pathophysiology. Finally, since RAMP-receptor interfaces are pharmacologically tractable, it may be possible to develop compounds targeting the RAMP1/CLR interface to assist in the treatment of asthma.