Repeated immune activation with low-dose lipopolysaccharide attenuates the severity of Huntington's disease in R6/2 transgenic mice.
Repeated immune activation with low-dose lipopolysaccharide attenuates the severity of Huntington's disease in R6/2 transgenic mice.
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DOI：
10.1080/19768354.2018.1473291
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发表时间：
2018
影响因子：
2.9
通讯作者：
Hong S
中科院分区：
文献类型：
--
作者：
Lee SW;Park HJ;Im W;Kim M;Hong S
亨廷顿病 (HD) 是一种由亨廷顿基因突变引起的神经退行性疾病。此前，据报道使用抗炎药物的治疗方法对于预防 HD 进展无效。由于免疫反应是否导致 HD 的发病尚不完全清楚，我们在此使用 R6/2 转基因 (Tg) HD 模型小鼠研究了免疫激活在 HD 中的作用。在 R6/2 Tg 小鼠的疾病阶段，先天免疫细胞（DC 和巨噬细胞）上 IL12 的产生和共刺激分子（例如 CD86 和 CD40）的表达减少。此外，这些小鼠中适应性 T 细胞（CD4+ 和 CD8+ T 细胞）的数量和效应记忆表型 CD4+ T 细胞的频率均减少。这些结果表明 HD 的严重程度与免疫系统受损密切相关，并且可能通过免疫系统的激活来逆转。由于脂多糖（LPS）是一种有效的 TLR4 激动剂，可激活免疫细胞，因此我们使用 LPS 评估了免疫激活对 HD 发病机制的影响。用低剂量 LPS 反复激活免疫，可显着将受损的免疫状态恢复至正常水平，并减轻 R6/2 Tg 小鼠疾病阶段的严重体重减轻和握紧表型增加，从而延长生存期。总而言之，这些结果强烈表明免疫激活对缓解 HD 病理具有有益影响，并可为 HD 提供新的治疗策略。
Huntington's disease (HD) is a neurodegenerative disorder caused by a mutation in the huntingtin gene. Previously, therapeutic approaches using anti-inflammatory agents were reportedly not effective for preventing HD progression. Since whether immune responses contribute to the onset of HD is not entirely understood, we herein investigated the role of immune activation in HD using the R6/2 transgenic (Tg) HD model mouse. IL12 production and the expression of costimulatory molecules (e.g. CD86 and CD40) on innate immune cells (DCs and macrophages) were diminished in the disease stage of R6/2 Tg mice. Moreover, the number of adaptive T cells (CD4+ and CD8+ T cells) and the frequency of effector memory phenotype CD4+ T cells were decreased in these mice. These results suggest that the severity of HD is closely related to an impaired immune system and might be reversed by activation of the immune system. Since lipopolysaccharide (LPS), a potent TLR4 agonist, activates immune cells, we evaluated the effect of immune activation on the pathogenesis of HD using LPS. The repeated immune activation with low-dose LPS significantly recovered the impaired immune status back to normal levels and attenuated both severe weight loss and the increased clasping phenotype found in the disease stage of R6/2 Tg mice, consequently resulting in prolonged survival. Taken together, these results strongly indicate that immune activation has beneficial influences on alleviating HD pathology and could provide new therapeutic strategies for HD.
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影响因子：
82.9
作者：
Chen, M;Ona, VO;Friedlander, RM
通讯作者：
Friedlander, RM
影响因子：
4.7
作者：
Zozulya, Alla L.;Clarkson, Benjamin D.;Ortler, Sonja;Fabry, Zsuzsanna;Wiendl, Heinz
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Wiendl, Heinz
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3.3
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影响因子：
3.7
作者：
Hindinger C;Bergmann CC;Hinton DR;Phares TW;Parra GI;Hussain S;Savarin C;Atkinson RD;Stohlman SA
通讯作者：
Stohlman SA
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作者：
Bastos, Leandro Francisco S.;Merlo, Leonardo A.;Coelho, Marcio M.
通讯作者：
Coelho, Marcio M.