Thymic Stromal Lymphopoietin Promotes MRGPRX2-Triggered Degranulation of Skin Mast Cells in a STAT5-Dependent Manner with Further Support from JNK.
Thymic Stromal Lymphopoietin Promotes MRGPRX2-Triggered Degranulation of Skin Mast Cells in a STAT5-Dependent Manner with Further Support from JNK.
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DOI：
10.3390/cells10010102
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发表时间：
2021-01-08
期刊：
影响因子：
6
通讯作者：
Zuberbier T
中科院分区：
文献类型：
--
作者：
Babina M;Wang Z;Franke K;Zuberbier T
胸腺基质淋巴细胞生成素 (TSLP) 由上皮细胞在稳态紊乱后释放，充当“警报器”和 Th2 免疫的驱动器。异常 TSLP 表达是特应性疾病的标志，包括特应性皮炎 (AD)。 AD 病变中肥大细胞 (MC) 过多，并显示脱颗粒迹象，但 TSLP 是否有助于颗粒排出仍不清楚。皮肤 MC 的脱颗粒通过两种主要途径进行，即 FcεRI 依赖性（过敏性）和 MRGPRX2 介导的（假性过敏性/神经源性）。越来越多的证据表明 MRGPRX2 在包括湿疹在内的皮肤病中可能至关重要。目前的研究表明 TSLP 是人类皮肤 MC 的一种新型启动因子。有趣的是，TSLP 选择性地与 MRGPRX2 配合以支持颗粒排出，同时它不影响自发或 FcεRI 驱动的胞吐作用。由化合物 48/80 或物质 P（两种典型的 MRGPRX2 激动剂）引发的 TSLP 辅助组胺释放伴随着 CD107a+ 细胞（MC 激活标记）的增加。然而，后一个过程的效力较差，并且只能在两个时间点中较晚的一个时间点检测到，这表明 TSLP 可能会延长颗粒的打开时间。从机制上讲，TSLP 引起皮肤 MC 中 STAT5 和 JNK 的磷酸化，并且增强的脱颗粒关键取决于 STAT5 活性，而 JNK 发挥了贡献作用。 RNA 干扰证实了药理抑制的结果，STAT5 的沉默完全消除了 TSLP 对 MRGPRX2 介导的脱颗粒的启动作用。总的来说，TSLP 是第一个有利于 MRGPRX2 而非 FcεRI 触发 MC 激活的因素。 TSLP、MC 和 MRGPRX2 与瘙痒症和特应性皮肤病理学的相关性表明所确定的联系具有广泛的影响。
Thymic stromal lymphopoietin (TSLP) is released by epithelial cells following disturbed homeostasis to act as “alarmin” and driver of Th2-immunity. Aberrant TSLP expression is a hallmark of atopic diseases, including atopic dermatitis (AD). Mast cells (MCs) are overabundant in AD lesions and show signs of degranulation, but it remains unknown whether TSLP contributes to granule discharge. Degranulation of skin MCs proceeds via two major routes, i.e., FcεRI-dependent (allergic) and MRGPRX2-mediated (pseudo-allergic/neurogenic). Evidence is accumulating that MRGPRX2 may be crucial in the context of skin diseases, including eczema. The current study reveals TSLP as a novel priming factor of human skin MCs. Interestingly, TSLP selectively cooperates with MRGPRX2 to support granule discharge, while it does not impact spontaneous or FcεRI-driven exocytosis. TSLP-assisted histamine liberation triggered by compound 48/80 or Substance P, two canonical MRGPRX2 agonists, was accompanied by an increase in CD107a+ cells (a MC activation marker). The latter process was less potent, however, and detectable only at the later of two time points, suggesting TSLP may prolong opening of the granules. Mechanistically, TSLP elicited phosphorylation of STAT5 and JNK in skin MCs and the reinforced degranulation critically depended on STAT5 activity, while JNK had a contributory role. Results from pharmacological inhibition were confirmed by RNA-interference, whereby silencing of STAT5 completely abolished the priming effect of TSLP on MRGPRX2-mediated degranulation. Collectively, TSLP is the first factor to favor MRGPRX2- over FcεRI-triggered MC activation. The relevance of TSLP, MCs and MRGPRX2 to pruritis and atopic skin pathology indicates broad repercussions of the identified connection.
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DOI：
10.1084/jem.20082242
发表时间：
2009-05-11
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Briot A;Deraison C;Lacroix M;Bonnart C;Robin A;Besson C;Dubus P;Hovnanian A
通讯作者：
Hovnanian A
DOI：
10.1084/jem.20062211
发表时间：
2007-02-19
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
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Delespesse G
影响因子：
3.6
作者：
Babina, Magda;Guhl, Sven;Zuberbier, Torsten
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Zuberbier, Torsten
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4.4
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影响因子：
3.8
作者：
Azzolina, A;Guarneri, P;Lampiasi, N
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Lampiasi, N