“丙戊酸表观调控巨噬细胞极化”控制重症肌无力相关炎症反应失衡的机制

Myasthenia Gravis (MG) is autoimmune disease with multiple causes. Disorder of inflammation has been found to strongly associate with the progression of MG. Macrophages are important cells of immune system which should polarize into M1 cells or M2 cells before functioning. M1 cells have the pro-inflammatory characteristic that promote inflammation through the secretion of pro-inflammatory cytokines and chemokines, while M2 cells perform anti-inflammatory ability with the release of anti-inflammatory cytokines and chemokines, meanwhile M2 cells are also involved in tissue remodeling. The balance between M1 and M2 cells is crucial to maintain inflammatory environment stable. Valproic Acid (VA) is a inhibitor of histone deacetylases. It can induce Macrophages polarize to M2 cells by means of inhibition of histone deacetylases and promote anti-inflammation activity. Our former study found the increase of a special subgroup of M1 cells in both the thymus and peripheral blood mononuclear cells which are obtained from MG patients, meanwhile the levels of related pro-inflammatory cytokines were elevated. This phenomenon implied that imbalance of M1 and M2 cells and the following inflammatory disorder might be one of the key factors in MG progression. For better understanding, On one hand we design a clinical study to identify the disorder of Macrophages polarization and related pro-inflammatory cytokines profile change in MG patients, and analyze the correlation between this disorder and MG symptoms. Then we will explain whether Thymectomy could improve the MG symptoms by correction of this disorder. On the other hand, we use VA to epigenetically regulate polarization of Macrophages which are both from MG patients and EAMG models in order to identify whether VA could promote Macrophages polarize into M2 cells. Further we will analyze the mechanism how this epigenetic regulation affects histone deacetylases, pivotal transcriptional factors and the level of downstream cytokines. Finally we will observe whether the using of VA in EAMG models could improve the symptoms and prognosis. Depending on this study, we will start to understand the potential value of Macrophages polarization inducing by epigenetic regulation to be a new method of MG treatments.

重症肌无力（MG）是一种多病因的自身免疫疾病，全身炎症反应失衡在MG的发生发展过程中具有关键作用。巨噬细胞通过向M1（促进炎症反应）或M2（抑制炎症反应和组织重塑）细胞极化发挥功能，M1/M2细胞平衡对维持炎症反应稳定具有重要作用。丙戊酸是广谱组蛋白脱乙酰化酶抑制剂，可通过抑制组蛋白乙酰化诱导巨噬细胞向M2转化，产生炎症抑制作用。我们前期研究发现MG患者胸腺和外周血存在一种特殊M1细胞亚群比例及相关促炎因子水平升高的现象，为此我们拟在临床上明确MG患者巨噬细胞极化和对应促炎因子分泌异常是否与MG症状相关联，分析胸腺切除是否可改善此异常。进一步阐明丙戊酸在细胞水平是否可表观调控促进MG源性巨噬细胞向M2极化，分析其对组蛋白脱乙酰化酶和关键转录因子的功能及下游炎症因子分泌的影响。最后在动物模型中了解这种调控对MG症状以及预后的影响，初步探讨通过表观调控巨噬细胞极化在MG治疗中的潜在价值。

重症肌无力（MG）是一种多病因的自身免疫疾病，全身炎症反应失衡在MG的发生发展过程中具有关键作用。前期研究发现巨噬细胞M1/M2极化失衡与MG的发生发展可能存在密切关系。丙戊酸（VA）是广谱组蛋白脱乙酰化酶抑制剂，可通过抑制组蛋白乙酰化诱导巨噬细胞向M2c极化，产生炎症抑制作用，对MG具有潜在的治疗价值。本研究拟在临床患者、细胞和动物水平了解MG患者巨噬细胞极化和相应细胞因子分泌与MG的关系。明确VA是否可调控MG相关巨噬细胞向M2c极化，以及对MG症状的影响。.主要研究内容：.检测MG患者外周血与胸腺组织中M1与M2c细胞的比例以及相关细胞因子水平，分析其与预后的关系；分析VA对动物MG模型（EAMG）源性巨噬细胞极化和功能的干预作用；了解VA对EAMG症状及M1/M2c极化的影响。.重要结果和关键数据：.MG患者外周血单核细胞（PBMCs）中M1细胞比例和相关促炎细胞因子水平升高、而趋化因子无明显差异，M2c细胞比例和相关抑炎细胞因子水平降低。在患者胸腺组织中也具有类似现象；VA在体外具有抑制EAMG源性静息巨噬细胞向M1细胞极化，同时诱导其向M2c细胞极化的功能，同时细胞内磷酸化STAT3下降、乙酰化STAT3上升；VA具有在EAMG体内抑制外周血静息巨噬细胞向M1细胞极化，并诱导其向M2c极化的作用，同时VA可改善EAMG的肌无力症状。.科学意义：. 本项目发现MG患者PBMCs和胸腺组织中存在M1/M2c的比例失衡，该现象引起促炎因子/抑炎因子的功能失衡，可能与MG的发生发展密切相关，对这种失衡的干预具有临床应用价值。VA在EAMG体外以及体内实验中均就有抑制巨噬细胞向M1极化并诱导其向M2c极化，从而调控EAMG全身炎症反应水平。VA对STAT3的乙酰化作用在巨噬细胞的极化调控中可能具有重要作用，值得进一步深入研究。VA对EAMG肌无力症状的改善提示其潜在临床应用价值。

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