Human Mas-Related G Protein-Coupled Receptors-X1 Induce Chemokine Receptor 2 Expression in Rat Dorsal Root Ganglia Neurons and Release of Chemokine Ligand 2 from the Human LAD-2 Mast Cell Line
Human Mas-Related G Protein-Coupled Receptors-X1 Induce Chemokine Receptor 2 Expression in Rat Dorsal Root Ganglia Neurons and Release of Chemokine Ligand 2 from the Human LAD-2 Mast Cell Line
复制标题
DOI：
10.1371/journal.pone.0058756
复制
发表时间：
2013-03-07
期刊：
影响因子：
3.7
通讯作者：
Breit, Andreas
中科院分区：
文献类型：
--
作者：
Solinski, Hans Juergen;Petermann, Franziska;Breit, Andreas
灵长类动物特异性Mas相关G蛋白偶联受体-X1(MRGPR-X1)在背根节(DRG)神经元中高度丰富，引起急性疼痛。在此，我们分析了MRGPR-X1对控制慢性疼痛各种标志物表达的血清反应因子(SRF)或活化T细胞核因子(NFAT)的影响。利用HEK293、DRG神经元源性F11细胞和培养的重组表达人MRGPR-X1的大鼠DRG神经元，我们发现SRF报告基因结构的激活和早期生长反应蛋白-1的诱导通过细胞外信号调节蛋白-1/2在炎性疼痛的发生中发挥重要作用。此外，我们观察到MRGPR-X1通过NFAT诱导趋化因子受体2(CCR2)上调，这被认为是神经病理性疼痛开始的关键事件，到目前为止，还没有任何内源性神经肽被描述。CCR2的上调通常与其内源性激动剂趋化因子配体2(CCL2)的释放增加有关。我们还发现MRGPR-X1在内源性表达MRGPR-X1的人结缔组织肥大细胞系中促进CCL2的释放。因此，我们首次提出证据表明，MRGPR-X1诱导DRG神经元中慢性疼痛标志物的表达，并提出了一个迄今尚未确定的信号通路，该信号通路通过作用于两种不同但功能协同的细胞类型来增强趋化因子信号。鉴于趋化因子信号在疼痛时序化中的重要作用，我们认为阻断这一信号通路可能是缓解趋化因子引起的疼痛的一种有前途的新策略。
Primate-specific Mas-related G protein-coupled receptors-X1 (MRGPR-X1) are highly enriched in dorsal root ganglia (DRG) neurons and induce acute pain. Herein, we analyzed effects of MRGPR-X1 on serum response factors (SRF) or nuclear factors of activated T cells (NFAT), which control expression of various markers of chronic pain. Using HEK293, DRG neuron-derived F11 cells and cultured rat DRG neurons recombinantly expressing human MRGPR-X1, we found activation of a SRF reporter gene construct and induction of the early growth response protein-1 via extracellular signal-regulated kinases-1/2 known to play a significant role in the development of inflammatory pain. Furthermore, we observed MRGPR-X1-induced upregulation of the chemokine receptor 2 (CCR2) via NFAT, which is considered as a key event in the onset of neuropathic pain and, so far, has not yet been described for any endogenous neuropeptide. Up-regulation of CCR2 is often associated with increased release of its endogenous agonist chemokine ligand 2 (CCL2). We also found MRGPR-X1-promoted release of CCL2 in a human connective tissue mast cell line endogenously expressing MRGPR-X1. Thus, we provide first evidence to suggest that MRGPR-X1 induce expression of chronic pain markers in DRG neurons and propose a so far unidentified signaling circuit that enhances chemokine signaling by acting on two distinct yet functionally co-operating cell types. Given the important role of chemokine signaling in pain chronification, we propose that interruption of this signaling circuit might be a promising new strategy to alleviate chemokine-promoted pain.