Ligand-independent function of β2-adrenergic receptor affects IgE-mediated Ca2+ influx in mast cells
Ligand-independent function of β2-adrenergic receptor affects IgE-mediated Ca2+ influx in mast cells
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DOI：
10.1016/j.bbrc.2024.150595
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发表时间：
2024-08-26
影响因子：
3.1
通讯作者：
Miyake，Sachiko
中科院分区：
文献类型：
--
作者：
Nagao，Kei;Yoshikawa，Soichiro;Miyake，Sachiko
背景肥大细胞是免疫球蛋白E（IgE）介导的过敏性炎症的关键效应细胞。与肥大细胞上的高亲和力IgE受体FcεRI结合的IgE的变应原交联触发信号级联，其激活信号蛋白并引起细胞外Ca 2+内流，这对细胞因子产生至关重要。肥大细胞上的β2-肾上腺素能受体（Adrb 2）负调节FcεRI信号传导，如通过Adrb 2激动剂抑制IgE/抗原（Ag）诱导的活化所证明的。尽管已知β2-肾上腺素能相关试剂影响肥大细胞功能，但Adrb 2在这些细胞中的特定内在作用尚未完全了解，可能是由于脱靶效应。本研究采用Adrb 2 −/−小鼠模型，通过检测骨髓来源的肥大细胞（BMMCs）表面肥大细胞标志物的表达、颗粒数量和肥大细胞蛋白酶基因的表达，探讨Adrb 2在肥大细胞中的作用，特别是Adrb 2在FcεRI信号转导中的作用。结果Adrb 2-/-不影响BMMCs的生成、肥大细胞表面标志物的表达、颗粒数量和肥大细胞蛋白酶的基因表达，表明Adrb 2的缺乏对肥大细胞的发育没有不良影响。然而，Adrb 2-/-BMMC在IgE/Ag刺激下表现出肿瘤坏死因子α（TNFα）产生减少和Ca 2+内流减少，这与NFAT易位减少相关。Adrb 2 −/−BMMCs中Adrb 2的恢复挽救了细胞因子的产生。结论Adrb 2具有非配体依赖性的增加肥大细胞内Ca 2+内流的功能。
BackgroundMast cells are key effector cells that elicit immunoglobulin E (IgE)-mediated allergic inflammations. Allergen cross-linking of IgE bound to the high-affinity IgE receptor, FcεRI, on mast cells triggers signaling cascades that activate signal proteins and evoke extracellular Ca2+influx, which are crucial for cytokine production. The β2-adrenergic receptor (Adrb2) on mast cells negatively regulates FcεRI signaling, as demonstrated by the inhibition of IgE/antigen (Ag)-induced activation by Adrb2 agonists.ObjectiveAlthough β2-adrenergic-related reagents are known to influence mast cell functions, the specific intrinsic role of Adrb2 in these cells is not fully understood, potentially because of off-target effects. In this study, the additional roles of Adrb2 in mast cells were investigated, specifically the involvement of Adrb2 in FcεRI signaling, usingAdrb2−/−mice.MethodsAdrb2−/−mice were used to investigate the roles of Adrb2 in mast cells by examining bone marrow-derived mast cells (BMMCs) for surface expression of mast cell markers, granule numbers, and gene expression of mast cell proteases. Cytokine production, Ca2+influx, and nuclear factor of activated T cells (NFAT) nuclear translocation were measured inAdrb2−/−andAdrb2+/+BMMCs upon IgE/Ag stimulation.ResultsAdrb2−/−did not affect the generation of BMMCs, their surface expression of mast cell markers, granule numbers, or gene expression of mast cell proteases, indicating that the absence of Adrb2 had no adverse effect on mast cell development. However,Adrb2−/−BMMCs exhibited reduced tumor necrosis factor α (TNFα) production and diminished Ca2⁺ influx upon IgE/Ag stimulation, which correlated with decreased NFAT translocation. Restoration of Adrb2 inAdrb2−/−BMMCs rescued cytokine production. Notably, FcεRI-mediated phosphorylation of the phospholipase PLCγ1 and mitogen-activated protein kinases (MAPKs) remained unchanged in the absence of Adrb2.ConclusionThese results suggest that Adrb2 has a novel ligand-independent function, increasing Ca2+entry in mast cells when stimulated with IgE/Ag.