Lewis Rebecca J, Chachi Latifa, Newby Chris, Amrani Yassine, Bradding Peter
Department of Infection, Immunity and Inflammation, Institute for Lung Health, University of Leicester, Leicester, UK.
J Immunol. 2016 Jan 1;196(1):55-63. doi: 10.4049/jimmunol.1402232. Epub 2015 Nov 25.
Human lung mast cells (HLMCs) play a central role in asthma pathogenesis through their relocation to the airway smooth muscle (ASM) bundles. β2 adrenoceptor (β2-AR)-agonists are used to relieve bronchoconstriction in asthma, but may reduce asthma control, particularly when used as monotherapy. We hypothesized that HLMC and human ASM cell (HASMC) responsiveness to β2-AR agonists would be attenuated when HLMCs are in contact with HASMCs. Cells were cultured in the presence of the short-acting β2-agonist albuterol, and the long-acting β2-agonists formoterol and olodaterol. Constitutive and FcεRI-dependent HLMC histamine release, HASMC contraction, and β2-AR phosphorylation at Tyr(350) were assessed. Constitutive HLMC histamine release was increased in HLMC-HASMC coculture and this was enhanced by β2-AR agonists. Inhibition of FcεRI-dependent HLMC mediator release by β2-agonists was greatly reduced in HLMC-HASMC coculture. These effects were reversed by neutralization of stem cell factor (SCF) or cell adhesion molecule 1 (CADM1). β2-AR agonists did not prevent HASMC contraction when HLMCs were present, but this was reversed by fluticasone. β2-AR phosphorylation at Tyr(350) occurred within 5 min in both HLMCs and HASMCs when the cells were cocultured, and was inhibited by neutralizing SCF or CADM1. HLMC interactions with HASMCs via CADM1 and Kit inhibit the potentially beneficial effects of β2-AR agonists on these cells via phosphorylation of the β2-AR. These results may explain the potentially adverse effects of β2-ARs agonists when used for asthma therapy. Targeting SCF and CADM1 may enhance β2-AR efficacy, particularly in corticosteroid-resistant patients.
人肺肥大细胞（HLMCs）通过迁移至气道平滑肌（ASM）束在哮喘发病机制中起核心作用。β2肾上腺素能受体（β2-AR）激动剂用于缓解哮喘中的支气管收缩，但可能会降低哮喘控制效果，尤其是用作单一疗法时。我们假设当HLMCs与人类ASM细胞（HASMCs）接触时，HLMC和HASMC对β2-AR激动剂的反应性会减弱。细胞在短效β2激动剂沙丁胺醇、长效β2激动剂福莫特罗和奥洛他定存在的情况下进行培养。评估了组成性和FcεRI依赖性HLMC组胺释放、HASMC收缩以及Tyr(350)处的β2-AR磷酸化。在HLMC-HASMC共培养中，组成性HLMC组胺释放增加，并且β2-AR激动剂可增强这种释放。在HLMC-HASMC共培养中，β2激动剂对FcεRI依赖性HLMC介质释放的抑制作用大大降低。通过中和干细胞因子（SCF）或细胞粘附分子1（CADM1）可逆转这些作用。当存在HLMCs时，β2-AR激动剂不能阻止HASMC收缩，但氟替卡松可逆转这种情况。当细胞共培养时，HLMCs和HASMCs中Tyr(350)处的β2-AR磷酸化在5分钟内发生，并且通过中和SCF或CADM1可抑制这种磷酸化。HLMCs通过CADM1和Kit与HASMCs的相互作用通过β2-AR磷酸化抑制了β2-AR激动剂对这些细胞的潜在有益作用。这些结果可能解释了β2-AR激动剂用于哮喘治疗时的潜在不良反应。靶向SCF和CADM1可能会增强β2-AR的疗效，尤其是在对皮质类固醇耐药的患者中。
