Laquinimod dampens hyperactive cytokine production in Huntington's disease patient myeloid cells.
Laquinimod dampens hyperactive cytokine production in Huntington's disease patient myeloid cells.
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DOI：
10.1111/jnc.13553
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发表时间：
2016-06
影响因子：
4.7
通讯作者：
Tabrizi SJ
中科院分区：
文献类型：
--
作者：
Dobson L;Träger U;Farmer R;Hayardeny L;Loupe P;Hayden MR;Tabrizi SJ
亨廷顿氏病（HD）是一种以脑和外周组织病理学为特征的神经退行性疾病。先天性免疫系统的过度活跃，部分是由于NFκB通路失调，是HD的早期和活跃成分。有证据表明，靶向免疫破坏可能会减缓疾病进展。拉喹莫德是一种口服活性免疫调节剂，通过调节NFκB信号传导下调外周血单核细胞中促炎细胞因子的产生，并下调脑中星形胶质细胞和小胶质细胞的活化。在两项III期临床试验中，拉喹莫德对多发性硬化症（MS）的炎症、脑萎缩和疾病进展具有有益作用。本研究调查了拉喹莫德对HD患者骨髓细胞培养物中过度活跃的促炎细胞因子释放和NFκB信号传导的影响。用拉奎莫德处理来自显症（manHD）和预显症（preHD）HD基因携带者和健康志愿者（HV）的单核细胞，并用脂多糖刺激。在用5 μM拉喹莫德预处理24小时后，manHD单核细胞响应于刺激释放较低水平的IL-1β、IL-5、IL-8、IL-10、IL-13和TNFα。PreHD单核细胞释放的IL-8、IL-10和IL-13水平较低，HV单核细胞中未观察到减少。在HD骨髓细胞中，通过κ B抑制剂（IκB）降解动力学、NFκB核转位以及IκB激酶（IKK）与HTT之间的相互作用来评估拉喹莫德对HD中NFκB信号传导功能障碍的影响。拉奎莫德治疗和未治疗条件之间没有观察到差异。这些结果提供了拉喹莫德抑制manHD和preHD单核细胞的高反应性细胞因子释放的证据，对HV单核细胞的影响大大降低。 有证据表明，靶向中枢神经系统和外周免疫破坏可能会减缓亨廷顿病（HD）的神经退行性过程。研究了拉喹莫德（一种口服活性免疫调节剂）对来自预显症和显症HD基因携带者和健康志愿者的刺激骨髓细胞培养物中过度活跃的细胞因子释放和功能失调的NFκB信号传导的影响。拉喹莫德抑制细胞因子释放，但不影响NFκB信号传导。阅读第670页上这篇文章的编辑摘要。
Huntington's disease (HD) is a neurodegenerative condition characterized by pathology in the brain and peripheral tissues. Hyperactivity of the innate immune system, due in part to NFκB pathway dysregulation, is an early and active component of HD. Evidence suggests targeting immune disruption may slow disease progression. Laquinimod is an orally active immunomodulator that down‐regulates proinflammatory cytokine production in peripheral blood mononuclear cells, and in the brain down‐regulates astrocytic and microglial activation by modulating NFκB signalling. Laquinimod had beneficial effects on inflammation, brain atrophy and disease progression in multiple sclerosis (MS) in two phase III clinical trials. This study investigated the effects of laquinimod on hyperactive proinflammatory cytokine release and NFκB signalling in HD patient myeloid cell cultures. Monocytes from manifest (manHD) and pre‐manifest (preHD) HD gene carriers and healthy volunteers (HV) were treated with laquinimod and stimulated with lipopolysaccharide. After 24 h pre‐treatment with 5 μM laquinimod, manHD monocytes released lower levels of IL‐1β, IL‐5, IL‐8, IL‐10, IL‐13 and TNFα in response to stimulation. PreHD monocytes released lower levels of IL‐8, IL‐10 and IL‐13, with no reduction observed in HV monocytes. The effects of laquinimod on dysfunctional NFκB signalling in HD was assessed by inhibitor of kappa B (IκB) degradation kinetics, nuclear translocation of NFκB and interactions between IκB kinase (IKK) and HTT, in HD myeloid cells. No differences were observed between laquinimod‐treated and untreated conditions. These results provide evidence that laquinimod dampens hyper‐reactive cytokine release from manHD and preHD monocytes, with a much reduced effect on HV monocytes. Evidence suggests targeting CNS and peripheral immune disruption may slow Huntington's disease (HD) neurodegenerative processes. The effects of laquinimod, an orally active immunomodulator, on hyperactive cytokine release and dysfunctional NFκB signalling in stimulated myeloid cell cultures from pre‐manifest and manifest HD gene carriers and healthy volunteers were investigated. Laquinimod dampened cytokine release but did not impact NFκB signalling. Read the Editorial Highlight for this article on page 670.