Combined anti-inflammatory effects of the endocannabinoid system and cortisol in arthritic tissue - a non-neuronal role of endocannabinoids

RA滑膜组织的特征是高水平的内源性大麻素anandamide，所有大麻素受体和主要内源性大麻素降解酶脂肪酸酰胺水解酶和Cox-2的表达。滑膜中大麻酰胺的来源尚不清楚。在大脑的某些区域，大麻胺水平和大麻素受体1水平由糖皮质激素控制。在长时间的压力下，糖皮质激素会导致anandamide的合成，从而抑制下丘脑-垂体-肾上腺轴的活动。在滑膜组织中，皮质醇通过细胞内胺的产生增加滑膜成纤维细胞对纤维连接蛋白的粘附。粘连是滑膜成纤维细胞迁移、软骨损伤和侵袭的关键。Anandamide激活大麻素受体1和2以及瞬时受体电位香草素1，所有这些都影响粘附。由于anandamide在RA滑膜中含量丰富，因此滑膜成纤维细胞可能是这种内源性大麻素的主要来源之一。胞外anandamide通过下调滑膜成纤维细胞的细胞因子/MMPs，抑制滑膜成纤维细胞增殖等不同途径发挥抗炎作用。到目前为止，尚不清楚皮质醇如何触发内源性大麻素的产生，以及这种相互作用是否可以用于治疗。此外，糖皮质激素如何调节大麻素受体，哪些其他因素诱导内源性大麻素合成，内源性大麻素系统如何发挥其抗炎作用，以及大麻素受体GPR18、GPR55和CB2如何影响滑膜成纤维细胞的功能尚不清楚。这些问题将在本项目中得到解答。

RA synovial tissue is characterized by high levels of the endocannabinoid anandamide, expression of all cannabinoid receptors and the major endocannabinoid degrading enzymes fatty acid amide hydrolase and Cox-2. The source of anandamide in synovium is still unclear. In certain brain areas, anandamide levels and cannabinoid receptor 1 levels are controlled by glucocorticoids. Upon prolonged stress, glucocorticoids lead to the synthesis of anandamide which dampens the activity of the hypothalamus-pituitary adrenal axis. In synovial tissue cortisol increases adhesion of synovial fibroblasts to fibronectin by the production of intracellular anandamide. Adhesion is crucial for synovial fibroblasts to initiate migration, cartilage damage and invasion. Anandamide activates cannabinoid receptors 1 and 2 as well as transient receptor potential vanilloid 1 all of which influence adhesion. Since anandamide is abundant in the RA synovium it is likely that synovial fibroblasts are one major source of this endocannabinoid. Extracellular anandamide exerts anti-inflammatory effects via different pathways by down-regulating cytokines/MMPs and inhibiting proliferation in synovial fibroblasts. Until now, it is unknown how cortisol triggers endocannabinoid production and whether this crosstalk can be exploited therapeutically. Furthermore it is unclear how glucocorticoids regulate cannabinoid receptors, which other factors induce endocannabinoid synthesis, how the endocannabinoid system exerts its anti-inflammatory action and how the cannabinoid receptors GPR18, GPR55 and CB2 influence the function of synovial fibroblasts. These points will be answered in this project.