5-羟色胺诱导的嗜酸粒细胞趋化及迁徙调节
2013/04/24
神经递质5-羟色胺（5-HT）是嗜酸粒细胞（Eos）的趋化因子，其与过敏性哮喘发病机制的关系通过以前的体内外实验已得到很好的认识。本研究在细胞和分子水平验证了5-HT诱导人及小鼠的Eos趋化及迁移作用的调节，发现过敏性患者的Eos及小鼠骨髓源性的Eos(BM-Eos)主要表达5-HT2A受体。在5-HT或DOI(一种5-HT2A/C选择性激动剂)暴露的环境里，可在体外层流条件下将人嗜酸粒细胞及AML14.3 D10人嗜酸粒细胞样细胞募集到血管细胞粘附分子表面，并伴随独特的细胞骨架和细胞形态改变及MAPK磷酸化。用特异性抑制剂阻断5-HT2A或ROCK MAPK, PI3K, PKC及钙调蛋白，而不是G（αi）-蛋白，可以阻止DOI所诱导的（嗜酸粒细胞）募集、肌动蛋白聚合作用以及VCAM-1粘附AML 14.3D10细胞的形态学改变。更多研究证实了5-HT在小鼠提睾肌微循环中，发炎的毛细血管后微静脉有促进BM-Eos募集的作用，并确证了5-HT2A信号通路下游的激活包括ROCK,MAPK, PI3K,PKC及钙调蛋白，与AML14.3D10细胞相似。DOI诱导的BM-Eos迁徙同样依赖于这些信号分子及钙离子。此外，DOI诱导的5-HT2A活化导致小鼠骨髓源性Eos细胞内钙离子浓度增高。总体来说，这些资料证明了5-HT（或DOI）/5-HT2A相互作用，通过促进肌动蛋白聚合作用来调节Eos趋化及迁徙，而肌动蛋白聚合作用与细胞形状或形态学改变有关，形态的改变有利于通过活化特异性细胞内信号分子（ROCK, MAPK, PI3K, PKC-钙调蛋白途径）促进细胞趋化及募集。
PLoS One. 2013;8(1):e54840. Epub 2013 Jan 23.
Regulation of Serotonin-Induced Trafficking and Migration of Eosinophils.
Kang BN, Ha SG, Bahaie NS, Hosseinkhani MR, Ge XN, Blumenthal MN, Rao SP, Sriramarao P.
Source
Laboratory of Allergic Diseases and Inflammation, Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, Minnesota, United States of America.
Abstract
Association of the neurotransmitter serotonin (5-HT) with the pathogenesis of allergic asthma is well recognized and its role as a chemoattractant for eosinophils (Eos) in vitro and in vivo has been previously demonstrated. Here we have examined the regulation of 5-HT-induced human and murine Eos trafficking and migration at a cellular and molecular level. Eos from allergic donors and bone marrow-derived murine Eos (BM-Eos) were found to predominantly express the 5-HT2A receptor. Exposure to 5-HT or 2,5-dimethoxy-4-iodoamphetamine (DOI), a 5-HT2A/C selective agonist, induced rolling of human Eos and AML14.3D10 human Eos-like cells on vascular cell adhesion molecule (VCAM)-1 under conditions of flow in vitro coupled with distinct cytoskeletal and cell shape changes as well as phosphorylation of MAPK. Blockade of 5-HT2A or of ROCK MAPK, PI3K, PKC and calmodulin, but not G(αi)-proteins, with specific inhibitors inhibited DOI-induced rolling, actin polymerization and changes in morphology of VCAM-1-adherent AML14.3D10 cells. More extensive studies with murine BM-Eos demonstrated the role of 5-HT in promoting rolling in vivo within inflamed post-capillary venules of the mouse cremaster microcirculation and confirmed that down-stream signaling of 5-HT2A activation involves ROCK, MAPK, PI3K, PKC and calmodulin similar to AML14.3D10 cells. DOI-induced migration of BM-Eos is also dependent on these signaling molecules and requires Ca(2+). Further , activation of 5-HT2A with DOI led to an increase in intracellular Ca(2+) levels in murine BM-Eos. Overall, these data demonstrate that 5-HT (or DOI)/5-HT2A interaction regulates Eos trafficking and migration by promoting actin polymerization associated with changes in cell shape/morphology that favor cellular trafficking and recruitment via activation of specific intracellular signaling molecules (ROCK, MAPK, PI3K and the PKC-calmodulin pathway).
PLoS One. 2013;8(1):e54840. Epub 2013 Jan 23.
PMID:23372779
