Table_1_G Protein-Coupled Receptor Kinase 2 (GRK2) Regulates T Cell Response in a Murine Model of House Dust Mite-Induced Asthma.docx

G protein-coupled receptor kinase 2 (GRK2) is an adapter protein that modulates G protein-coupled receptor (GPCR) signaling. It also regulates the functions and activity of other intracellular proteins in many cell types. Accordingly, GRK2 is thought to contribute to disease progression by a variety of mechanisms related to its multifunctional roles. Indeed, GRK2 levels are enhanced in patient samples as well as in preclinical models of several diseases. We have previously shown that GRK2 regulates mast cell functions, and thereby contributes to exacerbated inflammation during allergic reactions. In the current study, we observed that GRK2 levels are enhanced in the lungs of human asthma patients and in mice sensitized to house dust mite extract (HDME) allergen. Consistent with these findings, interleukin (IL)-4 and IL-13 levels were reduced in the lungs of GRK2+/− mice in a HMDE mouse model of asthma. Because Th2 cells are the major source of these cytokines during asthma, we determined the role of GRK2 in regulating T cell-specific responses in our HMDE mouse model. We observed a significant reduction of airway hyperresponsiveness (AHR), lung eosinophil and lymphocyte counts, serum IgE, Th2 cytokines (IL-4 and IL-13), goblet cell hyperplasia and mucus production in mice that had reduced GRK2 expression specifically in T cells. Collectively, our studies reveal an important role for GRK2 in regulating T cell response during asthma pathogenesis and further elucidation of the mechanisms through which GRK2 modulates airway inflammation will lead to the development of new therapeutic strategies for asthma.

G蛋白偶联受体激酶2（G protein-coupled receptor kinase 2, GRK2）是一种衔接蛋白，可调控G蛋白偶联受体（G protein-coupled receptor, GPCR）的信号转导。其还能调控多种细胞类型中其他胞内蛋白的功能与活性。据此，学界认为GRK2可通过与其多效性功能相关的多种机制参与疾病进程。事实上，在多种疾病的患者样本及临床前模型中，GRK2的表达水平均显著升高。我们此前的研究表明，GRK2可调控肥大细胞功能，进而在过敏反应期间加剧炎症反应。本研究中，我们观察到在哮喘患者的肺部及经屋尘螨提取物（house dust mite extract, HDME）过敏原致敏的小鼠肺部中，GRK2的表达水平均有所升高。与上述发现一致的是，在屋尘螨提取物诱导的哮喘小鼠模型中，GRK2杂合敲除（GRK2+/−）小鼠的肺部白细胞介素（interleukin, IL）-4与IL-13水平均有所降低。由于Th2细胞是哮喘发作期间这些细胞因子的主要来源，我们在该屋尘螨提取物小鼠模型中探究了GRK2对T细胞特异性应答的调控作用。我们发现，在T细胞特异性GRK2表达降低的小鼠中，气道高反应性（airway hyperresponsiveness, AHR）、肺部嗜酸性粒细胞与淋巴细胞计数、血清IgE水平、Th2型细胞因子（IL-4与IL-13）、杯状细胞增生及黏液分泌均显著降低。综上，本研究揭示了GRK2在哮喘发病过程中调控T细胞应答的重要作用；进一步阐明GRK2调控气道炎症的具体机制，将为哮喘治疗新策略的开发提供理论依据。