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

被引：175

作者：

Cloutier, Nathalie ^{[1
]}

Allaeys, Isabelle ^{[1
]}

Marcoux, Genevieve ^{[1
]}

Machlus, Kellie R. ^{[2
,3
]}

Mailhot, Benoit ^{[4
]}

Zufferey, Anne ^{[1
]}

Levesque, Tania ^{[1
]}

Becker, Yann ^{[1
]}

Tessandier, Nicolas ^{[1
]}

Melki, Imene ^{[1
]}

Zhi, Huiying ^{[5
]}

Poirier, Guy ^{[6
]}

Rondina, Matthew T. ^{[7
]}

Italiano, Joseph E. ^{[2
,3
]}

Flamand, Louis ^{[1
]}

McKenzie, Steven E. ^{[8
]}

Cote, Francine ^{[9
]}

Nieswandt, Bernhard ^{[10
,11
]}

Khan, Waliul I. ^{[12
,13
]}

Flick, Matthew J. ^{[14
]}

Newman, Peter J. ^{[5
]}

Lacroix, Steve ^{[4
]}

Fortin, Paul R. ^{[15
]}

Boilard, Eric ^{[1
,16
]}

机构：

[1] Univ Laval, Ctr Hosp Univ Quebec, Dept Microbiol & Immunol, Ctr Rech,Fac Med, Quebec City, PQ G1V 4G2, Canada

[2] Brigham & Womens Hosp, Dept Med, Div Hematol, Boston, MA 02115 USA

[3] Harvard Med Sch, Boston, MA 02115 USA

[4] Univ Laval, Ctr Hosp Univ Quebec, Dept Med Mol, Ctr Rech,Fac Med, Quebec City, PQ G1V 4G2, Canada

[5] Blood Res Inst, Milwaukee, WI 53213 USA

[6] Univ Laval, Ctr Hosp Univ Quebec, Dept Oncol, Ctr Rech,Fac Med, Quebec City, PQ G1V 4G2, Canada

[7] Univ Utah, Dept Internal Med, Salt Lake City, UT 84112 USA

[8] Thomas Jefferson Univ, Cardeza Fdn Hematol Res, Philadelphia, PA 19107 USA

[9] Univ Paris 05, CNRS ERL8254, Inst Imagine, Hop Necker,INSERM U1163, F-75006 Paris, France

[10] Univ Hosp, Dept Expt Biomed, D-97080 Wurzburg, Germany

[11] Rudolf Virchow Ctr, D-97080 Wurzburg, Germany

[12] McMaster Univ, Farncombe Family Digest Hlth Res Inst, Hamilton, ON L8S 4L8, Canada

[13] McMaster Univ, Dept Pathol & Mol Med, Hamilton, ON L8S 4L8, Canada

[14] Cincinnati Childrens Hosp, Canc & Blood Dis Inst, Div Expt Hematol & Canc Biol, Cincinnati, OH 45229 USA

[15] Univ Laval, Ctr Hosp Univ Quebec, Dept Med, Ctr Rech,Fac Med, Quebec City, PQ G1V 4G2, Canada

[16] Canadian Natl Transplantat Res Program, Edmonton, AB T6G 2E1, Canada

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2018年 / 115卷 / 07期

基金：

加拿大健康研究院;

关键词：

platelets; immune complexes; Fc receptor; serotonin; thrombocytopenia; FC-GAMMA-RIIA; INFLAMMATORY JOINT DISEASE; DEFICIENCY PROTECTS MICE; ACTIVATED PLATELETS; P-SELECTIN; IN-VITRO; RECEPTORS; SEPSIS; MOUSE; THROMBOCYTOPENIA;

D O I：

10.1073/pnas.1720553115

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 Fc gamma 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 alpha IIb beta 3 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.

引用

页码：E1550 / E1559

页数：10

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