Anti-inflammatory and immunomodulatory mechanisms of atorvastatin in a murine model of traumatic brain injury.
Anti-inflammatory and immunomodulatory mechanisms of atorvastatin in a murine model of traumatic brain injury.
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阿托伐他汀在小鼠脑外伤模型中的抗炎和免疫调节机制
DOI：
10.1186/s12974-017-0934-2
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发表时间：
2017-08-23
影响因子：
9.3
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Xu X;Gao W;Cheng S;Yin D;Li F;Wu Y;Sun D;Zhou S;Wang D;Zhang Y;Jiang R;Zhang J
背景神经炎症是创伤性脑损伤（traumatic brain injury，TBI）的一种重要的继发性损伤机制，在TBI的病理生理过程中具有有利和不利的双重作用。令人信服的数据表明，他汀类药物，一组降脂药物，也有广泛的免疫调节和抗炎特性。在他汀类药物中，阿托伐他汀已被证明是实验性TBI中的神经保护剂;然而，缺乏关于其在TBI急性期对神经炎症的影响的证据。本研究旨在评估阿托伐他汀治疗对调节免疫反应的影响，并探讨外周血白细胞侵袭和小胶质细胞/巨噬细胞极化在急性期post-TBI. MethodsC 57 BL/6小鼠进行TBI使用控制皮质撞击（CCI）设备。在TBI后1小时开始口服给予阿托伐他汀或载体盐水，连续三天。使用改良神经系统严重程度评分（mNSS）和Rota-rod评价短期神经功能缺损。通过流式细胞术和免疫组织化学分析脑侵入白细胞亚群。使用酶联免疫吸附试验（ELISA）检查促炎和抗炎细胞因子和趋化因子。然后通过定量实时PCR（qRT-PCR）和流式细胞术测定经典活化（M1）和交替活化（M2）小胶质细胞/巨噬细胞的标志物。神经元凋亡的双重染色的末端脱氧核苷酸转移酶-dUTP缺口末端标记（TUNEL）染色和免疫荧光标记的神经元核（NeuN）。结果急性治疗阿托伐他汀剂量为1 mg/kg/天显着减少神经元凋亡和改善行为缺陷。阿托伐他汀治疗后，T细胞、中性粒细胞和自然杀伤（NK）细胞的侵袭显著减弱，促炎细胞因子（IFN-γ和IL-6）和趋化因子（RANTES和IP-10）的产生也显著减弱。值得注意的是，阿托伐他汀治疗显著增加了外周脾和脑中调节性T细胞（T细胞）的比例，同时增加了其主要效应细胞因子IL-10和TGF-β1。我们还发现，阿托伐他汀显着衰减总的小胶质细胞/巨噬细胞的激活，但增加了M2/M1的比例，通过抑制M1极化和增强M2 polarization.ConclusionsOur数据表明，急性阿托伐他汀给药可以有效地调节脑外伤后的神经炎症，通过一种机制，涉及改变外周白细胞的侵袭和小胶质细胞/巨噬细胞的交替极化。
BackgroundNeuroinflammation is an important secondary injury mechanism that has dual beneficial and detrimental roles in the pathophysiology of traumatic brain injury (TBI). Compelling data indicate that statins, a group of lipid-lowering drugs, also have extensive immunomodulatory and anti-inflammatory properties. Among statins, atorvastatin has been demonstrated as a neuroprotective agent in experimental TBI; however, there is a lack of evidence regarding its effects on neuroinflammation during the acute phase of TBI. The current study aimed to evaluate the effects of atorvastatin therapy on modulating the immune reaction, and to explore the possible involvement of peripheral leukocyte invasion and microglia/macrophage polarization in the acute period post-TBI.MethodsC57BL/6 mice were subjected to TBI using a controlled cortical impact (CCI) device. Either atorvastatin or vehicle saline was administered orally starting 1 h post-TBI for three consecutive days. Short-term neurological deficits were evaluated using the modified neurological severity score (mNSS) and Rota-rod. Brain-invading leukocyte subpopulations were analyzed by flow cytometry and immunohistochemistry. Pro- and anti-inflammatory cytokines and chemokines were examined using enzyme-linked immunosorbent assay (ELISA). Markers of classically activated (M1) and alternatively activated (M2) microglia/macrophages were then determined by quantitative real-time PCR (qRT-PCR) and flow cytometry. Neuronal apoptosis was identified by double staining of terminal deoxynucleotidyl transferase-dUTP nick end labeling (TUNEL) staining and immunofluorescence labeling for neuronal nuclei (NeuN).ResultsAcute treatment with atorvastatin at doses of 1 mg/kg/day significantly reduced neuronal apoptosis and improved behavioral deficits. Invasions of T cells, neutrophils and natural killer (NK) cells were attenuated profoundly after atorvastatin therapy, as was the production of pro-inflammatory cytokines (IFN-γ and IL-6) and chemokines (RANTES and IP-10). Notably, atorvastatin treatment significantly increased the proportion of regulatory T cells (Tregs) in both the peripheral spleen and brain, and at the same time, increased their main effector cytokines IL-10 and TGF-β1. We also found that atorvastatin significantly attenuated total microglia/macrophage activation but augmented the M2/M1 ratio by both inhibiting M1 polarization and enhancing M2 polarization.ConclusionsOur data demonstrated that acute atorvastatin administration could modulate post-TBI neuroinflammation effectively, via a mechanism that involves altering peripheral leukocyte invasion and the alternative polarization of microglia/macrophages.
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