Peripheral serotonin causes dengue virus-induced thrombocytopenia through 5HT2 receptors
Peripheral serotonin causes dengue virus-induced thrombocytopenia through 5HT2 receptors
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DOI：
10.1182/blood-2018-08-869156
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发表时间：
2019-05-23
期刊：
影响因子：
20.3
通讯作者：
St John, Ashley L.
中科院分区：
文献类型：
--
作者：
Bin Masri, Mohamad Fadhli;Mantri, Chinmay Kumar;St John, Ashley L.
登革病毒（DENV）是最普遍的媒介传播的病毒病原体，每年感染数百万患者。血小板减少症，循环血小板计数减少，是DENV诱导疾病的最一致的体征，与疾病严重程度无关。然而，导致DENV诱导的血小板减少症的机制尚不清楚。在这里，我们表明，血小板减少症是由来自肥大细胞（MC），这是存在于血管周围空间的免疫细胞，是一个主要的外周来源的血清素。我们发现，在DENV感染期间，MCs释放5-羟色胺，其促进血小板活化、聚集和增强的吞噬作用，依赖于5 HT（2A）受体。小鼠MC缺乏或MC的药理学抑制可逆转血小板减少症。此外，重建的MC-缺陷型小鼠与野生型MC，但不是MC缺乏5-羟色胺合成的酶色氨酸羟化酶-1的缺陷所导致的，恢复了血小板减少的表型。外源性5-羟色胺也足以克服体外抑制血小板活化的药物的作用，并恢复DENV感染的MC缺陷小鼠的血小板减少症。在DENV感染期间靶向5 HT（2A）受体的治疗有效地预防了小鼠中的血小板减少症。类似地，源自DENV活化的人MC的5-羟色胺导致人血小板活化增加。因此，MC衍生的5-羟色胺是DENV诱导的血小板减少症的先前未鉴定的机制和潜在的治疗靶点。
Dengue virus (DENV) is the most prevalent vector-borne viral pathogen, infecting millions of patients annually. Thrombocytopenia, a reduction in circulating platelet counts, is the most consistent sign of DENV-induced disease, independent of disease severity. However, the mechanisms leading to DENV-induced thrombocytopenia are unknown. Here, we show that thrombocytopenia is caused by serotonin derived from mast cells (MCs), which are immune cells that are present in the perivascular space and are a major peripheral source of serotonin. We show that during DENV infection, MCs release serotonin, which prompts platelet activation, aggregation, and enhanced phagocytosis, dependent on 5HT(2A) receptors. MC deficiency in mice or pharmacologic inhibition of MCs reversed thrombocytopenia. Furthermore, reconstitution of MC-deficient mice with wild-type MCs, but not MCs lacking serotonin synthesis resulting from deficiency in the enzyme tryptophan hydroxylase-1, restored the thrombocytopenic phenotype. Exogenous serotonin was also sufficient to overcome the effects of drugs that inhibit platelet activation in vitro and to restore thrombocytopenia in DENV-infected MC-deficient mice. Therapeutic targeting of 5HT(2A) receptors during DENV infection effectively prevented thrombocytopenia in mice. Similarly, serotonin derived from DENV-activated human MCs led to increased human platelet activation. Thus, MC-derived serotonin is a previously unidentified mechanism of DENV-induced thrombocytopenia and a potential therapeutic target.