Platelets release pathogenic serotonin and return to circulation after immune complex-mediated sequestration

Proc Natl Acad Sci U S A. 2018 Feb 13;115(7):E1550-E1559. doi: 10.1073/pnas.1720553115. Epub 2018 Jan 31.


There is a growing appreciation for the contribution of platelets to immunity; however, our knowledge mostly relies on platelet functions associated with vascular injury and the prevention of bleeding. Circulating immune complexes (ICs) contribute to both chronic and acute inflammation in a multitude of clinical conditions. Herein, we scrutinized platelet responses to systemic ICs in the absence of tissue and endothelial wall injury. Platelet activation by circulating ICs through a mechanism requiring expression of platelet Fcγ receptor IIA resulted in the induction of systemic shock. IC-driven shock was dependent on release of serotonin from platelet-dense granules secondary to platelet outside-in signaling by αIIbβ3 and its ligand fibrinogen. While activated platelets sequestered in the lungs and leaky vasculature of the blood-brain barrier, platelets also sequestered in the absence of shock in mice lacking peripheral serotonin. Unexpectedly, platelets returned to the blood circulation with emptied granules and were thereby ineffective at promoting subsequent systemic shock, although they still underwent sequestration. We propose that in response to circulating ICs, platelets are a crucial mediator of the inflammatory response highly relevant to sepsis, viremia, and anaphylaxis. In addition, platelets recirculate after degranulation and sequestration, demonstrating that in adaptive immunity implicating antibody responses, activated platelets are longer lived than anticipated and may explain platelet count fluctuations in IC-driven diseases.

Keywords: Fc receptor; immune complexes; platelets; serotonin; thrombocytopenia.

Publication types

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

MeSH terms

  • Adult
  • Anaphylaxis / blood
  • Anaphylaxis / genetics
  • Anaphylaxis / immunology*
  • Animals
  • Antigen-Antibody Complex / immunology*
  • Blood Platelets / immunology*
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Platelet Activation
  • Platelet Count
  • Platelet Glycoprotein GPIIb-IIIa Complex / genetics
  • Platelet Glycoprotein GPIIb-IIIa Complex / immunology
  • Receptors, IgG / genetics
  • Receptors, IgG / immunology
  • Serotonin / immunology*
  • Shock, Septic / blood
  • Shock, Septic / genetics
  • Shock, Septic / immunology*
  • Young Adult


  • Antigen-Antibody Complex
  • Fc gamma receptor IIA
  • Platelet Glycoprotein GPIIb-IIIa Complex
  • Receptors, IgG
  • Serotonin