Pulmonary Neuroendocrine Cells Secrete γ-Aminobutyric Acid to Induce Goblet Cell Hyperplasia in Primate Models
Pulmonary Neuroendocrine Cells Secrete γ-Aminobutyric Acid to Induce Goblet Cell Hyperplasia in Primate Models
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DOI：
10.1165/rcmb.2018-0179oc
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发表时间：
2019-06-01
影响因子：
6.4
通讯作者：
Ai, Xingbin
中科院分区：
文献类型：
--
作者：
Barrios, Juliana;Kho, Alvin T.;Ai, Xingbin
粘液分泌过多是哮喘发病率和死亡率的主要原因。粘液过度产生是由多种因素的协调作用引起的，包括炎性细胞因子和γ-氨基丁酸（GABA）。GABA仅由小鼠肺中的肺神经内分泌细胞（PNEC）产生。最近在新生小鼠过敏性炎症模型中的研究表明，PNEC在GABA分泌过多引起的粘液过度产生中起重要作用。PNEC是否介导哮喘中粘液过度产生的GABA信号失调尚不清楚。在这项研究中，我们表征了非人灵长类动物和人类肺部GABA的细胞来源，并评估了灵长类动物疾病模型中GABA的分泌和信号传导。我们发现，与小鼠一样，PNEC是灵长类动物肺部GABA的主要来源。此外，婴儿非人灵长类动物哮喘模型表现出GABA分泌增加。此外，与健康对照组受试者相比，哮喘受试者气道上皮中GABA α型（GABA α）和β型（GABA β）受体的表达水平升高。最后，采用预诱导粘液过度产生的正常人支气管上皮细胞模型，我们显示GABA α和GABA β受体信号传导的药物阻断逆转了IL-13对MUC 5AC基因表达和杯状细胞增殖的作用。总之，我们的数据表明，在进化上保守的上皮内GABA信号，与IL-13，在粘液过度生产中起着至关重要的作用。我们的研究结果可能提供新的策略，以改善粘液分泌过多的哮喘患者通过靶向PNEC分泌和GABA信号。
Mucus overproduction is a major contributor to morbidity and mortality in asthma. Mucus overproduction is induced by orchestrated actions of multiple factors that include inflammatory cytokines and gamma-aminobutyric acid (GABA). GABA is produced only by pulmonary neuroendocrine cells (PNECs) in the mouse lung. Recent studies in a neonatal mouse model of allergic inflammation have shown that PNECs play an essential role in mucus overproduction by GABA hypersecretion. Whether PNECs mediate dysregulated GABA signaling for mucus overproduction in asthma is unknown. In this study, we characterized the cellular source of GABA in the lungs of nonhuman primates and humans and assessed GABA secretion and signaling in primate disease models. We found that like in mice, PNECs were the major source of GABA in primate lungs. In addition, an infant nonhuman primate model of asthma exhibited an increase in GABA secretion. Furthermore, subjects with asthma had elevated levels of expression of a subset of GABA type alpha (GABA alpha) and type beta (GABA beta) receptors in airway epithelium compared with those of healthy control subjects. Last, employing a normal human bronchial epithelial cell model of preinduced mucus overproduction, we showed pharmaceutical blockade of GABA alpha and GABA beta receptor signaling reversed the effect of IL-13 on MUC5AC gene expression and goblet cell proliferation. Together, our data demonstrate an evolutionarily conserved intraepithelial GABA signaling that, in concert with IL-13, plays an essential role in mucus overproduction. Our findings may offer new strategies to ameliorate mucus overproduction in patients with asthma by targeting PNEC secretion and GABA signaling.