Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands.
Ann Rheum Dis. 2010 Sep;69(9):1717-23. doi: 10.1136/ard.2009.118554. Epub 2010 May 28.
The alpha7 subunit of nicotinic acetylcholine receptors (alpha7nAChR) can negatively regulate the synthesis and release of proinflammatory cytokines by macrophages and fibroblast-like synoviocytes in vitro. In addition, stimulation of the alpha7nAChR can reduce the severity of arthritis in murine collagen-induced arthritis (CIA).
To provide more insight into the role of the alpha7nAChR in the pathogenesis of arthritis by investigating the effect of the absence of alpha7nAChR in CIA in alpha7-deficient (alpha7nAChR(-/-)) compared with wild-type (WT) mice.
CIA was induced in alpha7nAChR(-/-) and WT littermate mice at day 0 by immunisation with chicken collagen type II (cCII) followed by a booster injection with cCII on day 20. Mice were killed on day 44 or day 63 and arthritis activity as well as radiological and histological damage were scored. The effects on the immune response were evaluated by measurement of antigen-specific antibodies and cytokines, and evaluation of the effects on antigen-specific stimulated spleen cells.
In alpha7nAChR(-/-) mice a significant increase in the incidence and severity of arthritis as well as increased synovial inflammation and joint destruction were seen. Exacerbation of CIA was associated with elevated systemic proinflammatory cytokines and enhanced T-helper cell 1 (Th1)-cytokine and tumour necrosis factor alpha production by spleen cells. Moreover, a specific decrease in the collagen-specific 'Th1-associated' IgG2a response was seen, whereas IgG1 titres were unaffected.
The results presented here indicate that immune cell function in a model of rheumatoid arthritis is regulated by the cholinergic system and, at least in part, mediated by the alpha7nAChR.
烟碱型乙酰胆碱受体的α7 亚基（α7nAChR）在体外可以负向调节巨噬细胞和纤维样滑膜细胞中促炎细胞因子的合成和释放。此外，刺激α7nAChR 可以减轻胶原诱导关节炎（CIA）小鼠关节炎的严重程度。
通过研究 CIA 中α7nAChR 缺失（α7nAChR(-/-)）与野生型（WT）小鼠相比对关节炎发病机制的影响，为α7nAChR 在关节炎发病机制中的作用提供更多的见解。
在第 0 天通过用鸡胶原蛋白 II（cCII）免疫接种诱导 CIA，然后在第 20 天用 cCII 进行加强注射，在α7nAChR(-/-)和 WT 同窝仔鼠中诱导 CIA。在第 44 天或第 63 天处死小鼠，并对关节炎活动以及放射学和组织学损伤进行评分。通过测量抗原特异性抗体和细胞因子以及评估对抗原特异性刺激的脾细胞的影响来评估对免疫反应的影响。
在α7nAChR(-/-)小鼠中，关节炎的发生率和严重程度、滑膜炎症和关节破坏均显著增加。CIA 的加重与全身性促炎细胞因子的升高以及脾细胞中 Th1 细胞因子和肿瘤坏死因子α产生的增强有关。此外，胶原特异性“Th1 相关”IgG2a 反应明显下降，而 IgG1 滴度不受影响。
本文结果表明，在类风湿关节炎模型中，免疫细胞功能受胆碱能系统调节，至少部分通过α7nAChR 介导。
