Glial-derived neurotrophic factor regulates enteric mast cells and ameliorates dextran sulfate sodium-induced experimental colitis
Glial-derived neurotrophic factor regulates enteric mast cells and ameliorates dextran sulfate sodium-induced experimental colitis
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胶质源性神经营养因子调节肠肥大细胞并改善硫酸葡聚糖钠诱导的实验性结肠炎
DOI：
10.1016/j.intimp.2020.106638
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Qin Xie
中科院分区：
文献类型：
--
作者：
Qin Xie
背景与目的：尽管已有研究表明肠神经胶质细胞（EGCs）与肠肥大细胞之间的相互作用在炎症性肠病（IBD）的发病机制中发挥重要作用，但EGCs调节肠肥大细胞的确切机制仍不明确。本研究旨在探讨已证实主要由EGCs产生的胶质细胞源性神经营养因子（GDNF）是否可调节肠肥大细胞并改善葡聚糖硫酸钠（DSS）诱导的实验性结肠炎。
方法：将编码GDNF的重组腺病毒载体（Ad - GDNF）通过结肠内给药的方式应用于DSS诱导的实验性结肠炎模型。测定疾病活动指数和组织学评分。采用酶联免疫吸附试验（ELISA）检测肿瘤坏死因子 - α（TNF - α）、白细胞介素 - 6的表达水平以及髓过氧化物酶（MPO）活性。评估类胰蛋白酶和β - 氨基己糖苷酶的表达情况。检测GDNF特异性受体（GFR - α1/RET）。使用酶标仪检测钙离子内流情况。通过蛋白质免疫印迹试验（western blot assay）分析磷酸化c - Jun氨基末端激酶（p - JNK）的表达。
结果：GDNF通过与肥大细胞中的受体（GFR - α1/RET）结合，下调JNK信号通路，减少细胞内钙离子内流，进而抑制肠肥大细胞的活化，减少其脱颗粒现象以及促炎细胞因子的表达，而抗GDNF中和抗体处理可消除这些抑制作用。此外，给予GDNF可改善实验性结肠炎。
结论：GDNF能够调节肠肥大细胞并改善实验性结肠炎。GDNF可能是EGCs与肠肥大细胞之间相互交流的重要介质，并且GDNF可能是治疗IBD的一种有效药物。
Background & Aims: Although interactions between enteric glial cells (EGCs) and enteric mast cells have been demonstrated to play an important role in the pathogenesis of inflammatory bowel disease (IBD), the exact mechanisms by which EGCs regulate enteric mast cells are still unknown. The aims of this study were to investigate whether glial-derived neurotrophic factor (GDNF), which has been confirmed to be produced mostly by EGCs, might regulate enteric mast cells and ameliorate dextran sulfate sodium (DSS)-induced experimental colitis..Methods: Recombinant adenoviral vectors encoding GDNF (Ad-GDNF) were administered intracolonically in experimental colitis induced by DSS. The disease activity index and histological score were measured. The expression of tumour necrosis factor-α (TNF-α), interleukin-6 and myeloperoxidase (MPO) activity were measured.by ELISA assay. The expression of trypsin and β-hexosaminidase were evaluated. GDNF specific receptor (GFR-α1/RET) was detected. The calcium reflux was tested by microplate reader. The expression p-JNK was analyzed by western blot assay..Results: GDNF resulted in a significant inhibition of the activation of enteric mast cells by down-regulating JNK signal pathway, lessening intracellular calcium influx, and then reducing the degranulation as well as the expression of pro-inflammatory cytokines via combing with its receptor (GFR-α1/RET) in mast cells, and these.inhibitory effects were abrogated by treatment with neutralizing antibody against GDNF. Moreover, the administration of GDNF led to an amelioration of experimental colitis..Conclusions: GDNF are able to regulate enteric mast cells and ameliorate experimental colitis. GDNF might be an important mediator of the cross-talk between EGCs and enteric mast cells, and GDNF might be a useful therapeutic drug for IBD.