GRK2 differentially regulates FcεRI and MRGPRB2-mediated responses in mast cells.
GRK2 differentially regulates FcεRI and MRGPRB2-mediated responses in mast cells.
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DOI：
10.3389/fimmu.2023.1155777
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发表时间：
2023
影响因子：
7.3
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中科院分区：
文献类型：
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除了高亲和力的IgE受体（FcεRI）外，小鼠肥大细胞（MCs）的一个亚型还表达一种G蛋白偶联受体，称为mass相关G蛋白偶联受体(GPCR)-B2 （MRGPRB2；人类同源MRGPRX2）。GPCR激酶2 （GRK2）是一种丝氨酸/苏氨酸激酶，可磷酸化GPCR以促进其脱敏和内化。我们之前的研究表明，在小鼠骨髓源性MCs （BMMCs）中沉默GRK2表达可阻断ige介导的脱颗粒。化合物48/80 （C48/80）、P物质（SP）和LL-37分别通过MRGPRX2和MRGPRB2在人和小鼠MCs中引起脱粒。我们还报道了C48/80和SP引起MRGPRX2的脱敏和内化，但LL-37不会。在这里，我们制造了mc特异性缺失Grk2 （Cpa3Cre+/Grk2fl/fl）的小鼠，以确定其在ige介导的应答中的作用，并评估它是否在对LL-37、C48/80和SP的应答中差异调节脱粒。Grk2的缺失显著抑制了小鼠原发性肺源性MCs （PLMCs）中ige介导的STAT5酪氨酸磷酸化、钙动员和脱粒。相比之下，来自Cpa3Cre+/Grk2fl/fl小鼠的腹膜MCs （PMCs）对C48/80和SP的反应显示出显著的脱颗粒增强，但对LL-37没有反应。MCs中Grk2的缺失可减轻ige介导的被动皮肤过敏反应（PCA）和瘙痒，但不能减轻被动全身过敏反应（PSA）。令人惊讶的是，Mrgprb2-/-小鼠的PSA显著降低。这些发现表明GRK2与PCA和瘙痒有关，但与PSA无关。相比之下，GRK2使MRGPRX2/ b2介导的对C48/80和SP的反应脱敏，但对LL-37不敏感。然而，ige介导的PSA可能涉及LL-37或类似激动剂对MRGPRB2的激活，其功能不受GRK2的调节。
In addition to high-affinity IgE receptor (FcεRI), a subtype of mouse mast cells (MCs) expresses a G protein-coupled receptor known as Mas-related G protein-coupled receptor (GPCR)-B2 (MRGPRB2; human ortholog MRGPRX2). GPCR kinase 2 (GRK2) is a Serine/Threonine kinase that phosphorylates GPCRs to promote their desensitization and internalization. We previously showed that silencing GRK2 expression in mouse bone marrow-derived MCs (BMMCs) blocks IgE-mediated degranulation. Compound 48/80 (C48/80), substance P (SP) and LL-37 cause degranulation in human and mouse MCs via MRGPRX2 and MRGPRB2, respectively. We also reported that C48/80 and SP cause desensitization and internalization of MRGPRX2, but LL-37 does not. Here, we generated mice with MC-specific deletion of Grk2 (Cpa3Cre+/Grk2fl/fl ) to determine its role on IgE-mediated responses and to assess whether it differentially regulates degranulation in response to LL-37, C48/80 and SP. Absence of GRK2 substantially inhibited IgE-mediated tyrosine phosphorylation of STAT5, calcium mobilization, and degranulation in mouse primary lung-derived MCs (PLMCs). By contrast, peritoneal MCs (PMCs) from Cpa3Cre+/Grk2fl/fl mice demonstrated significant enhancement of degranulation in response to C48/80 and SP, but not LL-37. Deletion of Grk2 in MCs attenuated IgE-mediated passive cutaneous anaphylaxis (PCA) and itch but not passive systemic anaphylaxis (PSA). Surprisingly, PSA was significantly reduced in Mrgprb2-/- mice. These findings suggest that GRK2 contributes to PCA and itch but not PSA. By contrast, GRK2 desensitizes MRGPRX2/B2-mediated responses to C48/80 and SP but not LL-37. However, IgE-mediated PSA likely involves the activation of MRGPRB2 by LL-37 or a similar agonist, whose function is resistant to modulation by GRK2.
影响因子：
4.3
作者：
Kiwanuka KN;Motunrayo Kolawole E;Mcleod JJA;Baker B;Paez PA;Zellner MP;Haque TT;Paranjape A;Jackson K;Kee SA;Dailey J;Martin RK;Ryan JJ
通讯作者：
Ryan JJ