Expansion of Monocytic Myeloid-Derived Suppressor Cells in Patients Under Hemodialysis Might Lead to Cardiovascular and Cerebrovascular Events.
Expansion of Monocytic Myeloid-Derived Suppressor Cells in Patients Under Hemodialysis Might Lead to Cardiovascular and Cerebrovascular Events.
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DOI：
10.3389/fimmu.2020.577253
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发表时间：
2020
影响因子：
7.3
通讯作者：
Li X
中科院分区：
文献类型：
--
作者：
Xing YF;Cai JR;Qin JJ;Zhou WY;Li CM;Li X
终末期肾病背景下心脑血管病变的具体机制尚未阐明。在本研究中，我们研究了髓源性抑制细胞（MDSC）对血液透析患者的临床影响及其作用机制。在 104 名接受血液透析的患者中测试了 MDSC，并确定了它们与总生存期 (OS) 以及心脑血管事件的关联。与健康对照相比，血液透析患者的单核细胞 MDSC (M-MDSC) 水平显着升高。 M-MDSC 在 103 名血液透析患者中首次测试后 3 个月进行了测试，其中一名患者因过早死亡而没有重新测试。 M-MDSC水平的重复结果与初始结果一致。 M-MDSC 持续高水平的患者表现出 OS 降低，以及中风和急性心力衰竭事件增加。多变量 Cox 回归表明，M-MDSC 是血液透析患者 OS 和卒中事件的独立预测因子。血液透析相关的 M-MDSC 以剂量依赖性方式显着消除 T 细胞增殖。此外，与单核细胞相比，M-MDSC 表现出更高水平的 CXCR4 和 VLA-4，这表明它们被募集至动脉粥样硬化病变的能力增强。血液透析相关的 M-MDSC 中精氨酸酶 I 的表达和精氨酸酶的活性也显着升高。与单核细胞组相比，通过与 M-MDSC 共培养，人冠状动脉内皮细胞 (HCAEC) 表现出更高的迁移能力。精氨酸酶抑制剂和L-精氨酸消除了血液透析相关M-MDSC的免疫抑制功能和诱导HCAECs迁移。与健康对照相比，血液透析患者血浆 IFN-γ、TNF-α 和 IL-6 升高。血液透析患者M-MDSC水平与IL-6水平呈正相关。与健康捐献者的血浆相比，血液透析患者的血浆显着诱导M-MDSCs。此外，IL-6中和抗体显着消除了诱导。 IFN-γ和TNF-α的中和抗体部分减少了诱导的M-MDSC的精氨酸酶的产生。血液透析 ESRD 患者 M-MDSC 升高，且与心脑血管疾病风险密切相关。血液透析相关的 M-MDSC 增强了对动脉粥样硬化病变的募集，通过消耗局部 L-精氨酸促进内皮细胞的迁移。
The specific mechanism of cardiovascular and cerebrovascular vasculopathy in the context of end-stage renal disease has not been elucidated. In the present study, we investigated the clinical impact of myeloid-derived suppressor cells (MDSCs) on hemodialysis patients and their mechanism of action. MDSCs were tested among 104 patients undergoing hemodialysis and their association with overall survival (OS) and cardiovascular and cerebrovascular events was determined. Hemodialysis patients presented a significantly higher level of monocytic MDSCs (M-MDSCs) compared to healthy controls. M-MDSC were tested 3 months after first testing among 103 hemodialysis patients, with one patient not retested due to early death. The repeated results of M-MDSC levels were consistent with the initial results. Patients with persistent high level of M-MDSCs presented decreased OS, as well as increased stroke and acute heart failure events. As illustrated by multivariate Cox regression, M-MDSC was an independent predictor for OS and stroke events of hemodialysis patients. T cell proliferations were significantly abrogated by hemodialysis-related M-MDSCs in a dose-dependent manner. Besides, M-MDSCs presented higher levels of CXCR4 and VLA-4 compared to monocytes, which indicated their enhanced capability to be recruited to atherosclerotic lesions. The expression of arginase I and activity of arginase was also significantly raised in hemodialysis-related M-MDSCs. Human coronary arterial endothelial cells (HCAECs) presented increased capability to migration by coculture with M-MDSCs, compared with monocyte group. Arginase inhibitor and L-arginine abrogated the immune suppressive function and induction of HCAECs migration of hemodialysis related M-MDSC. Plasma IFN-γ, TNF-α and IL-6 were elevated in hemodialysis patients compared with healthy control. M-MDSC level was positively related to IL-6 level among hemodialysis patients. The plasma of hemodialysis patients induced M-MDSCs significantly compared with plasma from health donors. Besides, IL-6 neutralizing antibody significantly abrogated the induction. Neutralizing antibody of IFN-γ and TNF-α partially decreased the generation of arginase of the induced M-MDSC. M-MDSCs were elevated in ESRD patients under hemodialysis, and they exhibited a strong association with the risk of cardiovascular and cerebrovascular diseases. Hemodialysis related M-MDSC presented enhanced recruitment to atherosclerotic lesions, promoted the migration of endothelial cells through exhaustion of local L-arginine.