Abstract
The majority of peripheral serotonin is stored in platelets, which secrete it on activation. Serotonin releases Weibel-Palade bodies (WPBs) and we asked whether absence of platelet serotonin affects neutrophil recruitment in inflammatory responses. Tryptophan hydroxylase (Tph)1–deficient mice, lacking non-neuronal serotonin, showed mild leukocytosis compared with wild-type (WT), primarily driven by an elevated neutrophil count. Despite this, 50% fewer leukocytes rolled on unstimulated mesenteric venous endothelium of Tph1(-/-) mice. The velocity of rolling leukocytes was higher in Tph1(-/-) mice, indicating fewer selectin-mediated interactions with endothelium. Stimulation of endothelium with histamine, a secretagogue of WPBs, or injection of serotonin normalized the rolling in Tph1(-/-) mice. Diminished rolling in Tph1(-/-) mice resulted in reduced firm adhesion of leukocytes after lipopolysaccharide treatment. Blocking platelet serotonin uptake with fluoxetine in WT mice reduced serum serotonin by > 80% and similarly reduced leukocyte rolling and adhesion. Four hours after inflammatory stimulation, neutrophil extravasation into lung, peritoneum, and skin wounds was reduced in Tph1(-/-) mice, whereas in vitro neutrophil chemotaxis was independent of serotonin. Survival of lipopolysaccharide-induced endotoxic shock was improved in Tph1(-/-) mice. In conclusion, platelet serotonin promotes the recruitment of neutrophils in acute inflammation, supporting an important role for platelet serotonin in innate immunity.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Acute Disease
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Animals
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Blood Platelets / drug effects
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Blood Platelets / immunology*
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Blood Platelets / metabolism
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Chemotaxis / drug effects
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Chemotaxis / immunology
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Endothelium, Vascular / drug effects
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Endothelium, Vascular / immunology
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Endothelium, Vascular / metabolism
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Flow Cytometry
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Fluoxetine / immunology
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Fluoxetine / pharmacology
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Histamine / immunology
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Histamine / pharmacology
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Inflammation / genetics
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Inflammation / immunology*
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Inflammation / metabolism
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Kaplan-Meier Estimate
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L-Selectin / immunology
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L-Selectin / metabolism
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Leukocyte Rolling / drug effects
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Leukocyte Rolling / genetics
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Leukocyte Rolling / immunology
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Leukocytosis / genetics
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Leukocytosis / immunology
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Leukocytosis / metabolism
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Lipopolysaccharides
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Neutrophil Infiltration / immunology
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Neutrophils / drug effects
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Neutrophils / immunology*
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Neutrophils / metabolism
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Selective Serotonin Reuptake Inhibitors / immunology
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Selective Serotonin Reuptake Inhibitors / pharmacology
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Serotonin / blood
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Serotonin / immunology*
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Serotonin / metabolism
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Shock, Septic / chemically induced
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Shock, Septic / genetics
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Shock, Septic / immunology
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Tryptophan Hydroxylase / deficiency
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Tryptophan Hydroxylase / genetics
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Weibel-Palade Bodies / drug effects
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Weibel-Palade Bodies / immunology
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Weibel-Palade Bodies / metabolism
Substances
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Lipopolysaccharides
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Serotonin Uptake Inhibitors
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Fluoxetine
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L-Selectin
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Serotonin
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Histamine
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Tryptophan Hydroxylase