Upregulation of CD74 and its potential association with disease severity in subjects with ischemic stroke.
Upregulation of CD74 and its potential association with disease severity in subjects with ischemic stroke.
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DOI：
10.1016/j.neuint.2016.11.007
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发表时间：
2017-07
影响因子：
4.2
通讯作者：
Offner H
中科院分区：
文献类型：
--
作者：
Yang L;Kong Y;Ren H;Li M;Wei CJ;Shi E;Jin WN;Hao J;Vandenbark AA;Offner H
巨噬细胞移动抑制因子（MIF）是一个关键的细胞因子/趋化因子的激活和募集的炎症T淋巴细胞已知加剧实验性中风的严重程度。MIF效应通过其主要细胞受体CD 74介导，CD 74是存在于所有II类表达细胞（包括单核细胞、巨噬细胞和树突状细胞（DC））上的MHC II类不变链。我们以前证明，部分MHC II类/肽构建体（pMHC）可以有效地治疗实验性中风小鼠，部分是通过它们竞争性抑制MIF/CD 74相互作用和下游信号传导的能力。然而，MIF和CD 74在人类缺血性卒中中的作用尚未完全确定。为了评估pMHC的治疗潜力，我们评估了MIF和CD 74表达水平及其与缺血性卒中患者疾病结局的相关性。通过ELISA评估血浆中的MIF水平，并通过流式细胞术和qRT-PCR定量外周血单核细胞（PBMC）中的CD 74表达，所述外周血单核细胞（PBMC）获自缺血性卒中受试者以及年龄和性别匹配的健康对照（HC）。与HC相比，缺血性脑卒中患者血浆中MIF水平升高，PBMC中CD 74+细胞数量和CD 74 mRNA表达水平显著升高，主要表现在CD 4 + T细胞、单核细胞和DC上。皮质梗死与皮质下梗死相比，CD 74+细胞的增加更大，血液中CD 74+细胞的数量与梗死面积和神经功能结局密切相关。然而，MIF和CD 74表达的差异不受年龄、性别或病变偏侧性的影响。增加的CD 74表达水平可作为缺血性卒中受试者中卒中严重程度和预测结局恶化的有用生物标志物，并为未来使用pMHC构建体进行潜在治疗提供依据。
Macrophage migration inhibitory factor (MIF) is a key cytokine/chemokine in the activation and recruitment of inflammatory T lymphocytes known to exacerbate experimental stroke severity. MIF effects are mediated through its primary cellular receptor, CD74, the MHC class II invariant chain present on all class II expressing cells, including monocytes, macrophages and dendritic cells (DC). We demonstrated previously that partial MHC class II/peptide constructs (pMHC) can effectively treat mice with experimental stroke, in part through their ability to competitively inhibit MIF/CD74 interactions and downstream signaling. However, the role of MIF and CD74 in human ischemic stroke is not yet well established. To evaluate the therapeutic potential for pMHC, we assessed MIF and CD74 expression levels and their association with disease outcome in subjects with ischemic stroke. MIF levels were assessed in blood plasma by ELISA and CD74 expression was quantified by flow cytometry and qRT-PCR in peripheral blood mononuclear cells (PBMCs) obtained from subjects with ischemic stroke and age and sex-matched healthy controls (HC). MIF levels were increased in plasma and the number of CD74+ cells and CD74 mRNA expression levels were significantly increased in PBMC of subjects with ischemic stroke versus HC, mainly on CD4+ T cells, monocytes and DC. Greater increases of CD74+ cells were seen in subjects with cortical vs. subcortical infarcts and the number of CD74+ cells in blood correlated strongly with infarct size and neurological outcomes. However, differences in MIF and CD74 expression were not affected by age, gender or lesion laterality. Increased CD74 expression levels may serve as a useful biomarker for worse stroke severity and predicted outcomes in subjects with ischemic stroke and provide a rationale for potential future treatment with pMHC constructs.