Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH, USA.
Division of Biochemistry, National Institute of Nutrition, Hyderabad, Telangana, India.
Nat Commun. 2023 Dec 11;14(1):8207. doi: 10.1038/s41467-023-44040-1.
Asthma is a chronic inflammatory airway disease characterized by airway hyperresponsiveness (AHR), inflammation, and goblet cell hyperplasia. Multiple cytokines, including IFNγ, IL-4, and IL-13 are associated with asthma; however, the mechanisms underlying the effects of these cytokines remain unclear. Here, we report a significant increase in the expression of IL-31RA, but not its cognate ligand IL-31, in mouse models of allergic asthma. In support of this, IFNγ, IL-4, and IL-13 upregulated IL-31RA but not IL-31 in both human and mice primary airway smooth muscle cells (ASMC) isolated from the airways of murine and human lungs. Importantly, the loss of IL-31RA attenuated AHR but had no effect on inflammation and goblet cell hyperplasia in mice challenged with allergens or treated with IL-13 or IFNγ. We show that IL-31RA functions as a positive regulator of muscarinic acetylcholine receptor 3 expression, augmenting calcium levels and myosin light chain phosphorylation in human and murine ASMC. These findings identify a role for IL-31RA in AHR that is distinct from airway inflammation and goblet cell hyperplasia in asthma.
哮喘是一种慢性炎症性气道疾病,其特征是气道高反应性(AHR)、炎症和杯状细胞增生。多种细胞因子,包括 IFNγ、IL-4 和 IL-13,与哮喘有关;然而,这些细胞因子作用的机制尚不清楚。在这里,我们报告在过敏性哮喘的小鼠模型中,IL-31RA 的表达显著增加,但其同源配体 IL-31 没有增加。支持这一点的是,IFNγ、IL-4 和 IL-13 在从鼠和人肺部气道分离的人和小鼠原代气道平滑肌细胞(ASMC)中上调了 IL-31RA,但没有上调 IL-31。重要的是,IL-31RA 的缺失减弱了 AHR,但对过敏原刺激或用 IL-13 或 IFNγ 治疗的小鼠的炎症和杯状细胞增生没有影响。我们表明,IL-31RA 作为毒蕈碱乙酰胆碱受体 3 表达的正调节剂发挥作用,增加人和鼠 ASMC 中的钙水平和肌球蛋白轻链磷酸化。这些发现确定了 IL-31RA 在哮喘中 AHR 中的作用,与气道炎症和杯状细胞增生不同。
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