Department of Pharmacology, SBRI, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea.
Department of Neurology, SBRI, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea.
Toxicol Appl Pharmacol. 2018 Nov 1;358:10-22. doi: 10.1016/j.taap.2018.09.003. Epub 2018 Sep 5.
This study aimed to investigate the role of transglutaminase 2 (TG2) expressed in mast cells in substantia nigra (SN) in Parkinson's disease (PD) model or human PD patients. C57BL/6 mice received 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by ip injection to induce PD. Bone marrow-derived mast cells (BMMCs) were adoptively transferred to TG2 knockout (KO or TG2) mice by iv injection 1 day before MPTP injection or stimulated by 1 methyl-4-phenylpyridinium (MMP). KO-MPTP mice showed reduced expression of tyrosine hydroxylase (TH) and dopamine (DA) transporter (DAT) and loss of TH DA neurons, and expression of markers (c-kit, tryptase, FcεRI), mediators' release (histamine, leukotrienes, cytokines), and TG2 related to mast cells, and co-localization of DA neuronal cells and mast cells in SN tissues or release of mediators and TG2 activity in SN tissues and sera versus those in WT (wild type)-MPTP or BM + KO-MPTP mice. KO-MPTP mice reversed the alterations of behavior. KO-BMMCs-transferred KO-MPTP (BM + KO-MPTP) mice had restoration of all the responses versus the KO-MPTP mice. MPP-stimulated BMMCs had increased mediators' release, which were inhibited by TG2 inhibitor (R2 peptide). All the mediators and TG2 activity were also increased in the sera of human PD patients. The data suggest that TG2 expressed in mast cells recruited into SN tissues might contribute to neuroinflammation, which is known as one of the important features in pathogenesis of PD, via up-regulating the release of various mediators.
本研究旨在探讨肥大细胞中表达的转谷氨酰胺酶 2（TG2）在帕金森病（PD）模型或人类 PD 患者黑质（SN）中的作用。C57BL/6 小鼠通过腹腔注射 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导 PD。骨髓来源的肥大细胞（BMMCs）通过静脉注射在 MPTP 注射前 1 天被过继转移到 TG2 敲除（KO 或 TG2）小鼠中，或通过 1 甲基-4-苯基吡啶（MMP）刺激。KO-MPTP 小鼠表现出酪氨酸羟化酶（TH）和多巴胺（DA）转运体（DAT）表达减少以及 TH-DA 神经元丢失，以及肥大细胞标志物（c-kit、胰蛋白酶、FcεRI）、介质释放（组胺、白三烯、细胞因子）和与肥大细胞相关的 TG2 的表达，以及 SN 组织中 DA 神经元细胞和肥大细胞的共定位或 SN 组织和血清中介质和 TG2 活性的释放，与 WT（野生型）-MPTP 或 BM+KO-MPTP 小鼠相比。KO-MPTP 小鼠的行为改变得到逆转。KO-BMMCs 转移的 KO-MPTP（BM+KO-MPTP）小鼠与 KO-MPTP 小鼠相比，所有反应均得到恢复。MPP 刺激的 BMMCs 释放的介质增加，而 TG2 抑制剂（R2 肽）抑制了这些介质的释放。人类 PD 患者的血清中所有介质和 TG2 活性也增加。数据表明，募集到 SN 组织中的肥大细胞中表达的 TG2 可能通过上调各种介质的释放，导致神经炎症，这被认为是 PD 发病机制的重要特征之一。
