Mast Cell Biology Unit, Department of Dermatology and Allergy, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany.
Cells. 2021 Jan 8;10(1):102. doi: 10.3390/cells10010102.
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.
胸腺基质淋巴细胞生成素 (TSLP) 在稳态受到干扰后由上皮细胞释放，作为“警报素”和 Th2 免疫的驱动因素。异常的 TSLP 表达是特应性疾病的标志，包括特应性皮炎 (AD)。肥大细胞 (MCs) 在 AD 病变中过度丰富，并显示脱颗粒的迹象，但尚不清楚 TSLP 是否有助于颗粒释放。皮肤 MCs 的脱颗粒通过两条主要途径进行，即 FcεRI 依赖性（过敏）和 MRGPRX2 介导的（假性过敏/神经源性）。越来越多的证据表明，MRGPRX2 在皮肤病（包括湿疹）中可能至关重要。本研究揭示了 TSLP 是人类皮肤 MCs 的一种新型启动因子。有趣的是，TSLP 选择性地与 MRGPRX2 合作支持颗粒释放，而不影响自发或 FcεRI 驱动的胞吐作用。由化合物 48/80 或 P 物质触发的 TSLP 辅助组胺释放，这两种经典的 MRGPRX2 激动剂，伴随着 CD107a+细胞（MC 激活标志物）的增加。然而，后一过程较弱，并且仅在两个时间点中的较晚时间点才能检测到，这表明 TSLP 可能延长颗粒的开放时间。从机制上讲，TSLP 在皮肤 MCs 中引起 STAT5 和 JNK 的磷酸化，增强的脱颗粒作用严重依赖于 STAT5 活性，而 JNK 则具有辅助作用。通过 RNA 干扰确认了药理学抑制的结果，其中 STAT5 的沉默完全消除了 TSLP 对 MRGPRX2 介导的脱颗粒的启动作用。总之，TSLP 是第一个有利于 MRGPRX2 而非 FcεRI 触发的 MC 激活的因素。TSLP、MCs 和 MRGPRX2 与瘙痒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。
