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

TitlePlatelets release pathogenic serotonin and return to circulation after immune complex-mediated sequestration.
Publication TypeJournal Article
Year of Publication2018
AuthorsCloutier, N, Allaeys, I, Marcoux, G, Machlus, KR, Mailhot, B, Zufferey, A, Lévesque, T, Becker, Y, Tessandier, N, Melki, I, Zhi, H, Poirier, G, Rondina, MT, Italiano, JE, Flamand, L, McKenzie, SE, Cote, F, Nieswandt, B, Khan, WI, Flick, MJ, Newman, PJ, Lacroix, S, Fortin, PR, Boilard, E
JournalProc Natl Acad Sci U S A
Volume115
Issue7
PaginationE1550-E1559
Date Published2018 Feb 13
ISSN1091-6490
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.

DOI10.1073/pnas.1720553115
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID29386381
PubMed Central IDPMC5816207
Grant ListF32 HL118865 / HL / NHLBI NIH HHS / United States
U54 HL112311 / HL / NHLBI NIH HHS / United States
K01 DK111515 / DK / NIDDK NIH HHS / United States
R01 HL130054 / HL / NHLBI NIH HHS / United States
R01 AG048022 / AG / NIA NIH HHS / United States
R01 HL126547 / HL / NHLBI NIH HHS / United States
P01 HL110860 / HL / NHLBI NIH HHS / United States