Distinctive Roles for α7*- and α9*-Nicotinic Acetylcholine Receptors in Inflammatory and Autoimmune Responses in the Murine Experimental Autoimmune Encephalomyelitis Model of Multiple Sclerosis.
Distinctive Roles for α7*- and α9*-Nicotinic Acetylcholine Receptors in Inflammatory and Autoimmune Responses in the Murine Experimental Autoimmune Encephalomyelitis Model of Multiple Sclerosis.
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DOI：
10.3389/fncel.2017.00287
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发表时间：
2017
影响因子：
5.3
通讯作者：
Lukas RJ
中科院分区：
文献类型：
--
作者：
Liu Q;Whiteaker P;Morley BJ;Shi FD;Lukas RJ
先前的研究已经证明尼古丁具有免疫抑制和抗炎作用，包括在某些形式的多发性硬化症（MS）小鼠的实验性自身免疫性脑脊髓炎（EAE）模型中。其他使用基因敲除 (KO) 小鼠的研究表明，含有 α7、α9 或 β2 亚基（α7*-、α9*- 或 β2*-nAChR）的烟碱乙酰胆碱 (ACh) 受体参与不同的疾病恶化或疾病改善过程。这些结果与基因表达分析一致，显示许多类型的免疫系统细胞类型中都有 nAChR 亚基 mRNA。与对疾病状态的影响一致，nAChR 亚基（和亚型）KO 或尼古丁暴露对免疫细胞数量和分布以及细胞因子水平或免疫、炎症、脱髓鞘和轴突降解的其他标志物产生可预测的影响。为了支持我们关于 nAChR 亚型在 EAE 中独特作用的假设，我们使用了直接和过继的 EAE 诱导以及 nAChR 亚基基因双敲除 (DKO) 策略。通过对来自野生型 (WT) 小鼠的分离的 CD4+、CD8+、CD11b+ 和 CD11c+ 细胞进行免疫染色，证明了 nAChR α9 亚基作为蛋白质的免疫细胞表达，但在 nAChR α9 亚基 KO 动物的细胞中则不然。相对于 WT/媒介物处理的小鼠中观察到的效果，尼古丁暴露对 WT 或 α7/α9 DKO 动物中直接诱导的 EAE 具有保护作用，但值得注意的是，EAE 在媒介物处理的 α7/α9 DKO 小鼠中加剧。尽管尼古丁的保护作用在每种情况下都可见，但 DKO/媒介物中的脑损伤体积和颅内炎症活动同样高于 WT/媒介物治疗的动物。相比之下，在过继转移研究中，接受尼古丁而不是媒介物治疗的野生型动物脾细胞受体中，疾病严重程度减轻，疾病发作延迟。此外，在接受尼古丁处理的 WT 动物中观察到的保护作用与 nAChR α7/α9 DKO 小鼠脾细胞受体的保护作用相同，无论它们是否接触尼古丁或媒介物。与之前的观察相结合，这些发现与至少部分通过外周免疫细胞中的 α9*-nAChR 介导的疾病恶化（甚至诱导）一致。他们还提出了中枢神经系统 (CNS) α7*-nAChR 的保护作用。结果表明 α7*- 和 α9*-nAChR 都是调节炎症和自身免疫的治疗配体的潜在靶标。
Previous studies have demonstrated immunosuppressive and anti-inflammatory effects of nicotine, including in the experimental autoimmune encephalomyelitis (EAE) model in mice of some forms of multiple sclerosis (MS). Other studies using knock-out (KO) mice have implicated nicotinic acetylcholine (ACh) receptors containing α7, α9, or β2 subunits (α7*-, α9*- or β2*-nAChR) in different, disease-exacerbating or disease-ameliorating processes. These outcomes are in harmony with gene expression analyses showing nAChR subunit mRNA in many classes of immune system cell types. Consistent with influences on disease status, predictable effects of nAChR subunit (and subtype) KO, or of nicotine exposure, are seen on immune cell numbers and distribution and on cytokine levels or other markers of immunity, inflammation, demyelination, and axonal degradation. Providing support for our hypotheses about distinctive roles for nAChR subtypes in EAE, here we have used direct and adoptive EAE induction and a nAChR subunit gene double knock-out (DKO) strategy. Immune cell expression of nAChR α9 subunits as protein is demonstrated by immunostaining of isolated CD4+, CD8+, CD11b+ and CD11c+ cells from wild-type (WT) mice, but not in cells from nAChR α9 subunit KO animals. Nicotine exposure is protective against directly-induced EAE in WT or α7/α9 DKO animals relative to effects seen in WT/vehicle-treated mice, but, remarkably, EAE is exacerbated in vehicle-treated α7/α9 DKO mice. Brain lesion volume and intra-cranial inflammatory activity similarly are higher in DKO/vehicle than in WT/vehicle-treated animals, although nicotine’s protective effects are seen in each instance. By contrast, in adoptive transfer studies, disease severity is attenuated and disease onset is delayed in recipients of splenocytes from WT animals treated with nicotine rather than with vehicle. Moreover, protection as seen in nicotine-treated WT animals is the same in recipients of splenocytes from nAChR α7/α9 DKO mice irrespective of their exposure to nicotine or vehicle. When combined with previous observations, these findings are consistent with disease exacerbation (or even induction) being mediated at least in part via α9*-nAChR in peripheral immune cells. They also suggest protective roles of central nervous system (CNS) α7*-nAChR. The results suggest that both α7*- and α9*-nAChR are potential targets of therapeutic ligands to modulate inflammation and autoimmunity.
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影响因子：
9.9
作者：
Hedstrom, Anna K.;Baarnhielm, Maria;Alfredsson, Lars
通讯作者：
Alfredsson, Lars
影响因子：
3
作者：
Gentry, C. L.;Lukas, R. J.
通讯作者：
Lukas, R. J.
影响因子：
5.3
作者：
Liu, Qiang;Xie, Xitao;Wu, Jie
通讯作者：
Wu, Jie
DOI：
10.1084/jem.20092749
发表时间：
2010-08-30
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Hao J;Liu R;Piao W;Zhou Q;Vollmer TL;Campagnolo DI;Xiang R;La Cava A;Van Kaer L;Shi FD
通讯作者：
Shi FD
DOI：
10.1523/jneurosci.3952-08.2009
发表时间：
2009-01-28
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Liu Q;Huang Y;Xue F;Simard A;DeChon J;Li G;Zhang J;Lucero L;Wang M;Sierks M;Hu G;Chang Y;Lukas RJ;Wu J
通讯作者：
Wu J