Signaling through cannabinoid receptor 2 suppresses murine dendritic cell migration by inhibiting matrix metalloproteinase 9 expression
Signaling through cannabinoid receptor 2 suppresses murine dendritic cell migration by inhibiting matrix metalloproteinase 9 expression
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DOI：
10.1182/blood-2012-06-435362
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发表时间：
2012-11-01
期刊：
影响因子：
20.3
通讯作者：
Ganea, Doina
中科院分区：
文献类型：
--
作者：
Adhikary, Sabina;Kocieda, Virginia P.;Ganea, Doina
在炎症性疾病和自身免疫性疾病以及中枢神经系统损伤模型中给予大麻素受体2(CB2R)激动剂可显著减轻临床疾病，并减少炎症介质。先前的研究报道，CB2R信号也可以减少白细胞的迁移。树突状细胞(DC)向不同部位的迁移是激活它们和启动适应性免疫反应所必需的。在此，我们首次报道了CB2R信号在体外和体内影响DC迁移，主要是通过抑制基质金属蛋白酶9(MMP9)的表达。在Matrigel迁移实验中，树突状细胞产生的基质金属蛋白酶-9的减少导致体内和体外向引流淋巴结的迁移减少。这种作用是通过CB2R介导的，导致cAMP水平降低，随后ERK活性降低，c-Fos和c-jun与MMP-9启动子激活蛋白1结合减少。我们推测，通过抑制基质金属蛋白酶-9的产生和随后依赖基质金属蛋白酶-9的树突状细胞迁移，大麻素类物质有助于消解急性炎症和重建内环境平衡。选择性CB2R激动剂可能是未来有价值的治疗药物，通过靶向包括DC在内的活化免疫细胞来治疗慢性炎症性疾病。(血。2012；120(18)：3741-3749)
Administration of cannabinoid receptor 2 (CB2R) agonists in inflammatory and autoimmune disease and CNS injury models results in significant attenuation of clinical disease, and reduction of inflammatory mediators. Previous studies reported that CB2R signaling also reduces leukocyte migration. Migration of dendritic cells (DCs) to various sites is required for their activation and for the initiation of adaptive immune responses. Here, we report for the first time that CB2R signaling affects DC migration in vitro and in vivo, primarily through the inhibition of matrix metalloproteinase 9 (MMP-9) expression. Reduced MMP-9 production by DCs results in decreased migration to draining lymph nodes in vivo and in vitro in the matrigel migration assay. The effect on Mmp-9 expression is mediated through CB2R, resulting in reduction in cAMP levels, subsequent decrease in ERK activation, and reduced binding of c-Fos and c-Jun to Mmp-9 promoter activator protein 1 sites. We postulate that, by dampening production of MMP-9 and subsequent MMP-9-dependent DC migration, cannabinoids contribute to resolve acute inflammation and to reestablish homeostasis. Selective CB2R agonists might be valuable future therapeutic agents for the treatment of chronic inflammatory conditions by targeting activated immune cells, including DCs. (Blood. 2012;120(18):3741-3749)