Laboratory of Experimental Rheumatology and Neuroendocrine Immunology, Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany.
Ann Rheum Dis. 2012 Mar;71(3):432-9. doi: 10.1136/ard.2011.153056. Epub 2011 Sep 27.
As previously shown, the sympathetic nervous system (SNS) shows proinflammatory activity during initiation of arthritis but is anti-inflammatory in established collagen-induced arthritis (CIA). Interleukin 10 (IL-10)-producing B cells suppress arthritis and are a potential target of the SNS because (1) B cells express functional β(2)-adrenoceptors (β(2)ARs) and (2) IL-10, at least in monocytes/macrophages, is regulated in a cAMP/PKA/CREB-dependent manner.
To test the hypothesis that anti-inflammatory effects of the SNS in CIA are mediated by stimulating IL-10-producing anti-inflammatory B cells.
Collagen-induced arthritis in DBA/1 mice, sympathectomy, adoptive B cell transfer, in vitro B cell culture, and assessment of B cell IL-10 production.
Mice treated with B cells from SNS-intact mice showed less severe arthritis than mice treated with B cells from sympathectomised mice. This anti-inflammatory action of B cells from SNS-intact mice correlated with increased IL-10 produced by B cells, which was mediated by norepinephrine (NE), in a β(2)AR, PKA-dependent manner. However, an NE-mediated increase in IL-10 was seen only in B cells from immunised but not naive mice, explaining in part the anti-inflammatory properties of the SNS in the late phase of arthritis. Finally, animals treated with B cells isolated from immunised mice and activated in vitro in the presence of a β(2)AR stimulus showed a decrease in arthritis severity in comparison with controls, an approach that might be used for future cellular treatment strategies.
正如之前所显示的，在关节炎发作时，交感神经系统（SNS）表现出促炎活性，但在已建立的胶原诱导性关节炎（CIA）中具有抗炎作用。产生白细胞介素 10（IL-10）的 B 细胞可抑制关节炎，并且是 SNS 的潜在靶标，因为（1）B 细胞表达功能性β2-肾上腺素能受体（β2AR），（2）至少在单核细胞/巨噬细胞中，IL-10 的表达受 cAMP/PKA/CREB 依赖性调节。
测试 SNS 在 CIA 中的抗炎作用是通过刺激产生抗炎性白细胞介素 10 的抗炎性 B 细胞来介导的假设。
在 DBA/1 小鼠中进行胶原诱导性关节炎、交感神经切除术、过继性 B 细胞转移、体外 B 细胞培养以及 B 细胞 IL-10 产生的评估。
用来自 SNS 完整小鼠的 B 细胞治疗的小鼠关节炎比用来自交感神经切除小鼠的 B 细胞治疗的小鼠关节炎严重程度较轻。来自 SNS 完整小鼠的 B 细胞的这种抗炎作用与 B 细胞产生的白细胞介素 10 增加有关，这是通过β2AR、PKA 依赖性方式由去甲肾上腺素（NE）介导的。然而，仅在免疫而不是未免疫的小鼠的 B 细胞中观察到 NE 介导的 IL-10 增加，这部分解释了 SNS 在关节炎后期的抗炎特性。最后，用从免疫小鼠中分离并在体外用β2AR 刺激物激活的 B 细胞治疗的动物与对照组相比，关节炎严重程度降低，这种方法可能用于未来的细胞治疗策略。
