RETRACTED ARTICLE: Sepsis-induced elevation in plasma serotonin facilitates endothelial hyperpermeability

Abstract

Hyperpermeability of the endothelial barrier and resulting microvascular leakage are a hallmark of sepsis. Our studies describe the mechanism by which serotonin (5-HT) regulates the microvascular permeability during sepsis. The plasma 5-HT levels are significantly elevated in mice made septic by cecal ligation and puncture (CLP). 5-HT-induced permeability of endothelial cells was associated with the phosphorylation of p21 activating kinase (PAK1), PAK1-dependent phosphorylation of vimentin (P-vimentin) filaments, and a strong association between P-vimentin and ve-cadherin. These findings were in good agreement with the findings with the endothelial cells incubated in serum from CLP mice. In vivo, reducing the 5-HT uptake rates with the 5-HT transporter (SERT) inhibitor, paroxetine blocked renal microvascular leakage and the decline in microvascular perfusion. Importantly, mice that lack SERT showed significantly less microvascular dysfunction after CLP. Based on these data, we propose that the increased endothelial 5-HT uptake together with 5-HT signaling disrupts the endothelial barrier function in sepsis. Therefore, regulating intracellular 5-HT levels in endothelial cells represents a novel approach in improving sepsis-associated microvascular dysfunction and leakage. These new findings advance our understanding of the mechanisms underlying cellular responses to intracellular/extracellular 5-HT ratio in sepsis and refine current views of these signaling processes during sepsis.

Activation of the tryptophan/serotonin pathway is associated with severity and predicts outcomes in pneumonia: results of a long-term cohort study

“…From our results, it remains unclear why there was no evidence for increased 5-HT levels according to the severity of an infection. Possibly, inhibition by SERT-inhibitors could lower the peripheral levels of 5-HT [3]. Alternatively, pre-analytical issues and low metabolite stability could explain the lack of association.…”

“…Particularly TRP and its metabolites are thought to be altered during infections as part of the immune reaction [2,3]. There are two metabolic pathways in the breakdown of TRP [4] (illustrated in Figure 1).…”

“…However, recent studies have demonstrated its novel role as a strong inhibitor of T cell proliferation [2]. Sepsis-induced elevation of 5-HT has recently been discovered in a mouse model where high levels of 5-HT facilitated endothelial hyperpermeability [3]. Microvascular dysfunction is believed to contribute to patient mortality in sepsis [7].…”

“…Microvascular dysfunction is believed to contribute to patient mortality in sepsis [7]. Therefore an intervention with a 5-HT transporter inhibitor was speculated to be a potential therapeutic option [3].…”

Immuno-Thrombotic Effects of Platelet Serotonin

“…Indeed, platelet-derived 5-HT promotes leukocyte migration, possibly via activation of endothelial cells, thereby enhancing P-selectin exposure and IL-8 release [37], which trigger neutrophil rolling, adhesion, and extravasation. Moreover, locally increased levels of platelet-released 5-HT had paracrine effects on endothelial cells, thereby inducing microvasculature leakage through the activation of transglutaminase and the phosphorylation of vimentin [42]. By contrast, in solid tumors platelet-released 5-HT has been described as a major regulator of the tumor vascular homeostasis that continuously prevent bleeding.…”