Platelet serotonin promotes the recruitment of neutrophils to sites of acute inflammation in mice

Blood. 2013 Feb 7;121(6):1008-15. doi: 10.1182/blood-2012-06-437392. Epub 2012 Dec 12.

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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Animals
  • Blood Platelets / drug effects
  • Blood Platelets / immunology*
  • Blood Platelets / metabolism
  • Chemotaxis / drug effects
  • Chemotaxis / immunology
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / immunology
  • Endothelium, Vascular / metabolism
  • Flow Cytometry
  • Fluoxetine / immunology
  • Fluoxetine / pharmacology
  • Histamine / immunology
  • Histamine / pharmacology
  • Inflammation / genetics
  • Inflammation / immunology*
  • Inflammation / metabolism
  • Kaplan-Meier Estimate
  • L-Selectin / immunology
  • L-Selectin / metabolism
  • Leukocyte Rolling / drug effects
  • Leukocyte Rolling / genetics
  • Leukocyte Rolling / immunology
  • Leukocytosis / genetics
  • Leukocytosis / immunology
  • Leukocytosis / metabolism
  • Lipopolysaccharides
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neutrophil Infiltration / immunology
  • Neutrophils / drug effects
  • Neutrophils / immunology*
  • Neutrophils / metabolism
  • Serotonin / blood
  • Serotonin / immunology*
  • Serotonin / metabolism
  • Serotonin Uptake Inhibitors / immunology
  • Serotonin Uptake Inhibitors / pharmacology
  • Shock, Septic / chemically induced
  • Shock, Septic / genetics
  • Shock, Septic / immunology
  • Tryptophan Hydroxylase / deficiency
  • Tryptophan Hydroxylase / genetics
  • Weibel-Palade Bodies / drug effects
  • Weibel-Palade Bodies / immunology
  • Weibel-Palade Bodies / metabolism

Substances

  • Lipopolysaccharides
  • Serotonin Uptake Inhibitors
  • Fluoxetine
  • L-Selectin
  • Serotonin
  • Histamine
  • Tryptophan Hydroxylase