Simvastatin ameliorates experimental autoimmune encephalomyelitis by inhibiting Th1/Th17 response and cellular infiltration
Simvastatin ameliorates experimental autoimmune encephalomyelitis by inhibiting Th1/Th17 response and cellular infiltration
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DOI：
10.1007/s10787-015-0252-1
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发表时间：
2015-12-01
影响因子：
5.8
通讯作者：
Schatzmann Peron, Jean Pierre
中科院分区：
文献类型：
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作者：
de Oliveira, Daniel May;Lobato de Oliveira, Enedina Maria;Schatzmann Peron, Jean Pierre
实验性自身免疫性脑脊髓炎（EAE）是一种CD4（+）介导的中枢神经系统（CNS）自身免疫性病理，被用作研究人类神经炎性疾病多发性硬化症的模型。在EAE的发展过程中，自身反应性Th1和Th17 CD4(+) T细胞浸润中枢神经系统，促进炎症细胞募集、局灶性炎症和组织破坏。从这个意义上说，他汀类药物，用于降低脂质水平的药物，最近显示出有趣的免疫调节功能。事实上，他汀类药物促进了Th2反应的倾向，从而改善了EAE的临床结果。此外，辛伐他汀可以抑制Th17的分化。然而，他汀类药物对免疫系统的许多其他影响尚未明确，特别是在神经炎症期间。因此，本研究的目的是探讨辛伐他汀对实验性自身免疫性脑脊髓炎发展的影响。用MOG免疫小鼠（35-55），每日评估EAE严重程度并采用临床评分法评分。流式细胞术观察单核细胞浸润中枢神经系统后细胞因子的分泌情况。辛伐他汀（5mg /kg/d）改善临床预后，诱导tgf - β mRNA表达升高，抑制IL-6、IL-12p40、IL-12p70、RANTES和MIP-1 β分泌（p < 0.05）。这伴随着CNS炎性单核细胞浸润的显著减少，Th1和Th17细胞的频率均降低。辛伐他汀抑制T淋巴细胞与原代小胶质细胞共培养的增殖。辛伐他汀治疗通过抑制T细胞增殖和致病性Th1和Th17细胞的中枢神经系统浸润来促进EAE的临床改善。
Experimental autoimmune encephalomyelitis (EAE) is a CD4(+)-mediated autoimmune pathology of the central nervous system (CNS) that is used as a model for the study of the human neuroinflammatory disease, multiple sclerosis. During the development of EAE, auto-reactive Th1 and Th17 CD4(+) T cells infiltrate the CNS promoting inflammatory cells recruitment, focal inflammation and tissue destruction. In this sense, statins, agents used to lower lipid levels, have recently shown to exert interesting immunomodulatory function. In fact, statins promote a bias towards a Th2 response, which ameliorates the clinical outcome of EAE. Additionally, simvastatin can inhibit Th17 differentiation. However, many other effects exerted on the immune system by statins have yet to be clarified, in particular during neuroinflammation. Thus, the aim of this study was to investigate the effects of simvastatin on the development of experimental autoimmune encephalomyelitis.Mice were immunized with MOG(35-55) and EAE severity was assessed daily and scored using a clinical scale. Cytokine secretion by mononuclear cells infiltrating the CNS was evaluated by flow cytometry.Simvastatin (5 mg/kg/day) improved clinical outcome, induced an increase in TGF-beta mRNA expression and inhibited IL-6, IL-12p40, IL-12p70, RANTES and MIP-1 beta secretion (p < 0.05). This was accompanied by a significant decrease in CNS inflammatory mononuclear cell infiltration, with reduced frequencies of both Th1 and Th17 cells. Simvastatin inhibited the proliferation of T lymphocytes co-cultured with primary microglial cells.Simvastatin treatment promotes EAE clinical amelioration by inhibiting T cell proliferation and CNS infiltration by pathogenic Th1 and Th17 cells.