Department of Dermatology, University of Cologne, Cologne, Germany.
Institute for Medical Microbiology, Immunology and Hygiene and Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany.
Allergy. 2015 Jul;70(7):764-74. doi: 10.1111/all.12612. Epub 2015 Apr 16.
Mastocytosis is characterized by the accumulation of mast cells (MCs) associated with activating mutations of KIT. Tumor necrosis factor-related apoptosis-inducing ligand receptors (TRAIL-Rs) are preferentially expressed on neoplastic cells and induce the extrinsic apoptotic pathway. Recent studies reported on the expression of TRAIL-Rs and TRAIL-induced apoptosis in cultured human MCs, which depend on stem cell factor (SCF)-induced or constitutive KIT activation.
We sought to further define the impact of TRAIL-Rs on MCs in vivo and in vitro. Using Cre/loxP recombination, we generated mice with MC-specific and ubiquitous knockout of TRAIL-R. In these mice, anaphylaxis and numbers of MCs were investigated. We also explored the expression and function of TRAIL-Rs in cultured murine and human MCs upon activation of KIT. By conducting immunofluorescence staining, we analyzed the expression of TRAIL-Rs in MCs infiltrating the bone marrow of patients with mastocytosis.
MC-specific deletion of TRAIL-R was associated with a slight, but significant increase in anaphylaxis. Numbers of MCs in MC-specific knockouts of TRAIL-R were comparable to controls. Whereas cultured IL-3-dependent murine MCs from wild-type mice were resistant to TRAIL-induced apoptosis, SCF-stimulated MCs underwent apoptosis in response to TRAIL. Interestingly, activating KIT mutations also promoted sensitivity to TRAIL-mediated apoptosis in human MCs. In line with these findings, MCs infiltrating the bone marrow of patients with mastocytosis expressed TRAIL-R1.
Activation of KIT regulates the function of TRAIL-Rs in MCs. TRAIL-R1 may represent an attractive diagnostic and therapeutic target in diseases associated with KIT mutations, such as mastocytosis.
肥大细胞增多症的特征是肥大细胞（MCs）的积累，与 KIT 的激活突变有关。肿瘤坏死因子相关凋亡诱导配体受体（TRAIL-Rs）优先表达在肿瘤细胞上，并诱导外在凋亡途径。最近的研究报告了 TRAIL-Rs 的表达和 TRAIL 诱导的培养的人类 MCs 中的凋亡，这依赖于干细胞因子（SCF）诱导或组成型 KIT 激活。
我们试图进一步定义 TRAIL-Rs 对体内和体外 MCs 的影响。我们使用 Cre/loxP 重组，生成了 MC 特异性和普遍的 TRAIL-R 敲除小鼠。在这些小鼠中，研究了过敏反应和 MCs 的数量。我们还探讨了 KIT 激活后培养的小鼠和人类 MCs 中 TRAIL-Rs 的表达和功能。通过进行免疫荧光染色，我们分析了肥大细胞增多症患者骨髓浸润的 MCs 中 TRAIL-Rs 的表达。
MC 特异性 TRAIL-R 缺失与过敏反应略有但显著增加有关。MC 特异性 TRAIL-R 敲除小鼠的 MCs 数量与对照组相当。虽然来自野生型小鼠的依赖 IL-3 的培养的 MCs 对 TRAIL 诱导的凋亡具有抗性，但 SCF 刺激的 MCs 对 TRAIL 发生凋亡。有趣的是，激活的 KIT 突变也促进了人类 MCs 对 TRAIL 介导的凋亡的敏感性。与这些发现一致，肥大细胞增多症患者骨髓浸润的 MCs 表达 TRAIL-R1。
KIT 的激活调节 MCs 中 TRAIL-Rs 的功能。TRAIL-R1 可能代表与 KIT 突变相关的疾病（如肥大细胞增多症）的有吸引力的诊断和治疗靶点。
