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

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

Author information

1
Centre de Recherche du Centre Hospitalier Universitaire de Québec-Université Laval, Département de microbiologie et immunologie, Faculté de Médecine, Université Laval, QC, Canada G1V 4G2.
2
Division of Hematology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115.
3
Centre de Recherche du Centre Hospitalier Universitaire de Québec-Université Laval, Département de Médecine Moléculaire, Faculté de Médecine, Université Laval, QC, Canada G1V 4G2.
4
Blood Research Institute, Milwaukee, WI 53213.
5
Centre de Recherche du Centre Hospitalier Universitaire de Québec-Université Laval, Département d'Oncologie, Faculté de Médecine, Université Laval, QC, Canada G1V 4G2.
6
Department of Internal Medicine, University of Utah, Salt Lake City, UT 84112.
7
Cardeza Foundation for Hematological Research, Thomas Jefferson University, Philadelphia, PA 19107.
8
Institut Imagine, INSERM U1163, CNRS ERL8254, Université Paris Descartes, Hôpital Necker, 75006 Paris, France.
9
Department of Experimental Biomedicine, University Hospital and Rudolf Virchow Center, 97080 Wuerzburg, Germany.
10
Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada L8S 4L8.
11
Department of Pathology & Molecular Medicine, McMaster University, Hamilton, ON, Canada L8S 4L8.
12
Cancer and Blood Diseases Institute, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital, Cincinnati, OH 45229.
13
Centre de recherche du Centre Hospitalier Universitaire de Québec-Université Laval, Département de médecine, Faculté de médecine, Université Laval, QC, Canada G1V 4G2.
14
Centre de Recherche du Centre Hospitalier Universitaire de Québec-Université Laval, Département de microbiologie et immunologie, Faculté de Médecine, Université Laval, QC, Canada G1V 4G2; eric.boilard@crchudequebec.ulaval.ca.
15
Canadian National Transplantation Research Program, Edmonton, AB, Canada T6G 2E1.

Abstract

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

PMID:
29386381
PMCID:
PMC5816207
DOI:
10.1073/pnas.1720553115
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Conflict of interest statement: J.E.I. has a financial interest in and is a founder of Platelet BioGenesis, a company that aims to produce donor-independent human platelets from human-induced pluripotent stem cells at scale. J.E.I. is an inventor on this patent. The interests of J.E.I. were reviewed and are managed by the Brigham and Women’s Hospital and Partners HealthCare in accordance with their conflict of interest policies.

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