Atorvastatin restores imbalance of cluster of differentiation 4 (CD4)+ T cells in immune thrombocytopenia in vivo and in vitro
Atorvastatin restores imbalance of cluster of differentiation 4 (CD4)+ T cells in immune thrombocytopenia in vivo and in vitro
复制标题
阿托伐他汀在体内和体外恢复免疫性血小板减少症中分化簇 4 (CD4) T 细胞的不平衡
DOI：
10.1111/bjh.17938
复制
发表时间：
2021-11-25
影响因子：
6.5
通讯作者：
Xu，Miao
中科院分区：
文献类型：
--
作者：
Xu，Pengcheng;Zhao，Yajing;Xu，Miao
免疫性血小板减少症（ITP）是一种自身免疫性出血性疾病，其中T细胞的过度活化在发病机制中至关重要。阿托伐他汀（AT）是一种降脂药物，在某些炎症条件下显示出有希望的免疫调节作用。然而，AT在ITP中的免疫调节作用仍然难以捉摸。为探讨AT对ITP的治疗作用，从ITP患者中分离CD 4 +T细胞，并与不同剂量的AT共同培养。我们发现AT在体外能显著抑制细胞增殖，导致细胞周期阻滞，诱导细胞凋亡，并抑制CD 4 +T细胞的活化。建立ITP小鼠模型，结果显示AT治疗导致血小板计数更快恢复正常，并表现出相当的免疫调节功能。此外，我们还发现AT处理后，哺乳动物雷帕霉素靶蛋白（mTOR）、蛋白激酶B（AKT）和细胞外信号调节激酶（ERK）的磷酸化以及大鼠肉瘤病毒（RAS）的活化均显著降低。综上所述，我们的研究表明，AT可以通过RAS/丝裂原活化蛋白激酶激酶（MEK）/ERK和mTOR/磷脂酰肌醇-3激酶（PI 3 K）/AKT通路抑制ITP中CD 4 + T细胞的过度活化、增殖和存活，从而恢复CD 4 + T细胞的功能。因此，我们建议AT可以通过恢复过度激活的细胞免疫来作为ITP的潜在治疗选择。
Immune thrombocytopenia (ITP) is an autoimmune haemorrhagic disease, in which the overactivation of T cells is crucial in the pathogenesis. Atorvastatin (AT), a lipid‐lowering medicine, has shown promising immunomodulatory effects in certain inflammatory conditions. However, the immunoregulatory role of AT in ITP remains elusive. To investigate the effect of AT in the treatment of ITP, cluster of differentiation 4 (CD4)+T cells were isolated from patients with ITP and cultured with different dosages of AT. We found that AT significantly inhibited cell proliferation, led to cell cycle arrest, induced apoptosis, and repressed the activation of CD4+T cellsin vitro. ITP murine models were then established, and results showed that AT treatment led to faster recovery of the platelet count to normal and exhibited comparable immunomodulatory function. Furthermore, we found the phosphorylation of mammalian target of rapamycin (mTOR), protein kinase B (AKT) and extracellular signal‐regulated kinase (ERK), as well as activation of rat sarcoma virus (RAS) were all reduced dramatically after AT treatmentin vitro. In conclusion, our present study demonstrated that AT could reinstate the functions of CD4+T cells by inhibiting the excessive activation, proliferation, and survival of CD4+T cells in ITP via the RAS/mitogen‐activated protein kinase kinase (MEK)/ERK and the mTOR/phosphatidylinositol‐3 kinase (PI3K)/AKT pathway. Therefore, we propose that AT could be used as a potential therapeutic option for ITP by restoring the over‐activated cellular immunity.