Peripheral serotonin causes dengue virus–induced thrombocytopenia through 5HT2 receptors

Abstract

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 5HT2A 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 5HT2A 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.

From Classical to Unconventional: The Immune Receptors Facilitating Platelet Responses to Infection and Inflammation

“…5HT2A: Few studies also present 5-hydroxytryptamine 2A receptor (commonly known as serotonin or 5HT2A receptor) as a mediator of platelet responses to infections. 5HT2A receptor is a GPCR widely known to regulate platelet physiology [ 178 ]. Due to the significant role of serotonin in regulation of the central nervous system, a major portion of the studies involving 5HT2A is focused on psychological disorders and few studies have reported the immunoregulatory functions of serotonin [ 178 ].…”

“…5HT2A receptor is a GPCR widely known to regulate platelet physiology [ 178 ]. Due to the significant role of serotonin in regulation of the central nervous system, a major portion of the studies involving 5HT2A is focused on psychological disorders and few studies have reported the immunoregulatory functions of serotonin [ 178 ]. Recently, it was shown that serotonin generated from mast cells during dengue infections acts on platelets through 5HT2A receptor, leading to their activation and aggregation with eventual thrombocytopenia [ 178 ].…”

“…Due to the significant role of serotonin in regulation of the central nervous system, a major portion of the studies involving 5HT2A is focused on psychological disorders and few studies have reported the immunoregulatory functions of serotonin [ 178 ]. Recently, it was shown that serotonin generated from mast cells during dengue infections acts on platelets through 5HT2A receptor, leading to their activation and aggregation with eventual thrombocytopenia [ 178 ]. Moreover, this is associated with a positive feedback loop as platelets store large concentrations of serotonin in their dense granules which is released upon platelet activation [ 178 ].…”

“…Recently, it was shown that serotonin generated from mast cells during dengue infections acts on platelets through 5HT2A receptor, leading to their activation and aggregation with eventual thrombocytopenia [ 178 ]. Moreover, this is associated with a positive feedback loop as platelets store large concentrations of serotonin in their dense granules which is released upon platelet activation [ 178 ]. This also places platelets in a central position to deliver serotonin to other inflammatory effector cells including macrophages, microglia, mast cells, neutrophils, and dendritic cells [ 178 ].…”

“…Moreover, this is associated with a positive feedback loop as platelets store large concentrations of serotonin in their dense granules which is released upon platelet activation [ 178 ]. This also places platelets in a central position to deliver serotonin to other inflammatory effector cells including macrophages, microglia, mast cells, neutrophils, and dendritic cells [ 178 ]. The use of drugs such as ketanserin, which inhibits 5HT2A receptors, were also shown to protect mice from thrombocytopenia during DENV infection [ 178 ].…”