The Serotonin-Immune Axis in Preeclampsia

Abstract

Purpose of review: To review the literature and detail the potential immune mechanisms by which hyperserotonemia may drive pro-inflammation in preeclampsia and to provide insights into potential avenues for therapeutic discovery.

Recent findings: Preeclampsia is a severe hypertensive complication of pregnancy associated with significant maternal and fetal risk. Though it lacks any effective treatment aside from delivery of the fetus and placenta, recent work suggests that targeting serotonin systems may be one effective therapeutic avenue. Serotonin dysregulation underlies multiple domains of physiologic dysfunction in preeclampsia, including vascular hyporeactivity and excess platelet aggregation. Broadly, serotonin is increased across maternal and placental domains, driven by decreased catabolism and increased availability of tryptophan precursor. Pro-inflammation, another hallmark of the disease, may drive hyperserotonemia in preeclampsia. Interactions between immunologic dysfunction and hyperserotonemia in preeclampsia depend on multiple mechanisms, which we discuss in the present review. These include altered immune cell, kynurenine pathway metabolism, and aberrant cytokine production mechanisms, which we detail. Future work may leverage animal and in vitro models to reveal serotonin targets in the context of preeclampsia's immune biology, and ultimately to mitigate vascular and platelet dysfunction in the disease. Hyperserotonemia in preeclampsia drives pro-inflammation via metabolic, immune cell, and cytokine-based mechanisms. These immune mechanisms may be targeted to treat vascular and platelet endophenotypes in preeclampsia.

Keywords: Immunology; Inflammation; Obstetrics; Preeclampsia; Pregnancy; Serotonin.

Fig. 1. Serotonin is dysregulated across maternal, placenta, and fetal domains in preeclampsia.

A) Plasma tryptophan is increased in preeclampsia, while the kynurenine-to-tryptophan ratio is decreased [12] in some but not all patients [33] and kynurenine synthesis by indoleamine 2,3 dioxygenase is decreased [13, 34]. Increased tryptophan ultimately increases maternal plasma 5-HT in preeclampsia [–37] and gestational hypertension [38, 39], though whole serum 5-HT is decreased in preeclampsia and HELLP (hemolysis, elevated liver enzymes, low platelet count) syndrome. Decreased MAOA in plasma and platelets further leads to blunted production and urine excretion of 5-HIAA [35]. In the preeclamptic placenta, tryptophan [33], IDO [33, 34], and kynurenine [33] are decreased, demonstrating tryptophan preference for the serotonin over kynurenine pathway. B) Placental serotonin is significantly increased in preeclampsia [37], increases which are positively correlated with blood pressure and disease severity [8]. Placental MAOA (protein and enzymatic activity) is decreased in preeclampsia, possibly contributing to increased placental serotonin [40], with greater MAOA deficits associated with more severe disease (preeclampsia versus eclampsia) [8]. Decreased serotonin catabolism in placental syncytiotrophoblasts also contributes to increased placental serotonin [41]. Despite increased serotonin in preeclampsia, fetal serotonin transport may be unaffected. Placental serotonin transporter (SERT) gene (SLC6A4) and protein expression [42, 43], as well as functional 5-HT transport by syncytiotrophoblasts [41], are unchanged in preeclampsia. C) Umbilical artery or vein tryptophan is unchanged in preeclampsia, though whole cord blood 5-HT is increased in severe cases while 5-HIAA-to-5-HT ratio is decreased [44]. Conversely, umbilical vein 5-HT and 5-HIAA are decreased in gestational hypertension [38], likely due to impaired 5-HT catabolism by MAOA [44, 45]. 5-HIAA is increased in umbilical cord blood in both mild disease (gestational hypertension) [38] and in severe preeclampsia [44]

Fig. 2. Hypothesized mechanism by which hyperserotonemia drives pro-inflammation in preeclampsia.

A) Persistent serotonergic disruptions in the context of preeclampsia—namely, hyperserotonemia across maternal, placental, and fetal domains—may be due to initiating factors such as physiologic stress. Serotonin binds T cells and initiates downstream cascades through serotonin receptors (5-HTR), which are G protein-coupled receptors. Regulators of G-protein signaling (RGS), such as RGS2, modulate intracellular cascades and therefore inflammatory protein production. Inflammatory proteins including cytokines have impacts on vascular and platelet function and can contribute to further dysfunction in the setting of preeclampsia. Vascular and platelet dysfunction also feed-forward to increase circulating serotonin and signaling at the level of the T cell. B) Decreased maternal and placental IDO expression, which is modulated by inflammation, pushes tryptophan towards increased serotonin production in preeclampsia