Role of the cholinergic nervous system in rheumatoid arthritis: aggravation of arthritis in nicotinic acetylcholine receptor α7 subunit gene knockout mice
Role of the cholinergic nervous system in rheumatoid arthritis: aggravation of arthritis in nicotinic acetylcholine receptor α7 subunit gene knockout mice
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DOI：
10.1136/ard.2009.118554
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发表时间：
2010-05
影响因子：
27.4
通讯作者：
Marjolein A van Maanen;S. P. Stoof;G. Larosa;M. Vervoordeldonk;P. Tak
中科院分区：
文献类型：
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作者：
Marjolein A van Maanen;S. P. Stoof;G. Larosa;M. Vervoordeldonk;P. Tak
研究背景烟碱型乙酰胆碱受体α7亚基（α 7 nAChR）对巨噬细胞和成纤维样滑膜细胞合成和释放炎性细胞因子具有负性调节作用。此外，刺激α 7 nAChR可以减轻小鼠胶原诱导关节炎（CIA）中关节炎的严重程度。目的比较α 7-nAChR-/-小鼠CIA中α 7-nAChR缺失对关节炎发病的影响，进一步探讨α 7-nAChR在关节炎发病中的作用。方法用鸡II型胶原（cCII）免疫α 7 nAChR-/-和WT同窝小鼠，在第0天诱导CIA，然后在第20天加强注射cCII。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价对抗原特异性刺激的脾细胞的影响来评价对免疫应答的影响。结果α 7 nAChR-/-小鼠关节炎的发生率和严重程度明显增加，滑膜炎症和关节破坏明显增加。CIA的加重与全身促炎细胞因子升高和脾细胞产生的T辅助细胞1（Th 1）-细胞因子和肿瘤坏死因子α增强相关。此外，胶原特异性的“Th 1相关”IgG 2a反应的特异性降低，而IgG 1滴度不受影响。结论类风湿关节炎模型中免疫细胞的功能受胆碱能系统的调节，至少部分是由α 7 nAChR介导的。
Background The α7 subunit of nicotinic acetylcholine receptors (α7nAChR) can negatively regulate the synthesis and release of proinflammatory cytokines by macrophages and fibroblast-like synoviocytes in vitro. In addition, stimulation of the α7nAChR can reduce the severity of arthritis in murine collagen-induced arthritis (CIA). Objective To provide more insight into the role of the α7nAChR in the pathogenesis of arthritis by investigating the effect of the absence of α7nAChR in CIA in α7-deficient (α7nAChR-/-) compared with wild-type (WT) mice. Methods CIA was induced in α7nAChR-/- 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. Results In α7nAChR-/- 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 α production by spleen cells. Moreover, a specific decrease in the collagen-specific ‘Th1-associated’ IgG2a response was seen, whereas IgG1 titres were unaffected. Conclusions 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 α7nAChR.