Satria Rahmat Dani, Jhan Ming-Kai, Chen Chia-Ling, Tseng Po-Chun, Wang Yung-Ting, Lin Chiou-Feng
International Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan.
Department of Clinical Pathology and Laboratory Medicine, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, 55281, Indonesia.
J Inflamm Res. 2022 Mar 5;15:1717-1728. doi: 10.2147/JIR.S356742. eCollection 2022.
Infection with dengue virus (DENV) causes hematological complications in dengue diseases characterized by thrombocytopenia accompanied by macrophage activation syndrome and hemophagocytosis in fatal patients.
In this study, we investigate the undefined mechanisms underlying the progression of thrombocytopenia caused by thrombophagocytosis based on an ex vivo whole-blood co-culture model of DENV infection for mimicking the acute febrile phase of infection.
In this model, complete blood count test showed a decrease in monocytes ( < 0.01), but not neutrophils nor other white blood cells, accompanied by a low thrombocyte count ( < 0.01) in DENV infection with a positive correlation ( = 0.636, < 0.05). Furthermore, DENV exposure caused significant thrombophagocytosis in mononuclear cells ( < 0.05). Abnormal production of tumor necrosis factor (TNF)-α was highly associated with induction of thrombophagocytosis ( = 0.758, < 0.01), decreased monocytes ( = -0.758, < 0.01), and decreased thrombocyte ( = -0.728, < 0.01). Neutralizing TNF-α considerably ( < 0.05) reversed such DENV-induced effects and was further validated by immunostaining-based flow cytometry analysis on mononuclear CD14 positive monocytes. Exogenous administration of TNF-α effectively caused thrombophagocytosis accompanied by decreased monocytes and thrombocytes, probably causing monocyte activation.
These results demonstrate the potential pathogenesis of thrombocytopenia caused by TNF-α-induced thrombophagocytosis in monocytes during DENV infection.
登革病毒（DENV）感染会导致登革热疾病出现血液学并发症，其特征为血小板减少，在致命患者中还伴有巨噬细胞活化综合征和噬血细胞现象。
在本研究中，我们基于DENV感染的体外全血共培养模型来模拟感染的急性发热期，研究由噬血作用导致血小板减少进展的未知机制。
在该模型中，全血细胞计数检测显示，DENV感染时单核细胞减少（<0.01），但中性粒细胞及其他白细胞未减少，同时伴有低血小板计数（<0.01），二者呈正相关（=0.636，<0.05）。此外，DENV暴露导致单核细胞中出现显著的噬血现象（<0.05）。肿瘤坏死因子（TNF）-α的异常产生与噬血作用的诱导高度相关（=0.758，<0.01）、单核细胞减少（=-0.758，<0.01）以及血小板减少（=-0.728，<0.01）。中和TNF-α可显著（<0.05）逆转DENV诱导的此类效应，基于单核细胞CD14阳性单核细胞的免疫染色流式细胞术分析进一步验证了这一点。外源性给予TNF-α可有效导致噬血现象，同时伴有单核细胞和血小板减少，可能导致单核细胞活化。
这些结果证明了DENV感染期间TNF-α诱导单核细胞噬血作用导致血小板减少的潜在发病机制。
