期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 115, 期 7, 页码 E1550-E1559出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1720553115
关键词
platelets; immune complexes; Fc receptor; serotonin; thrombocytopenia
资金
- Canadian Institutes of Health Research (CIHR)
- NIH/National Heart, Lung, and Blood Institute [5F32HL118865, HL130054, R01H168130]
- National Institutes of Diabetes and Digestive and Kidney Diseases [1K01DK111515]
- Canadian Funds for Innovation
- National Institute on Aging [AG048022]
- CIHR foundation grant
- CIHR operating grant
- CIHR Grant [MOP 93575]
- CIHR
- Canadian Blood Services
- Arthritis Society
- TAS
- Fondation du Centre Hospitalier Universitaire de Quebec
- George E. Wahlen Veterans Affairs Medical Center
- [HL112311]
- [HL126547]
- [P01HL110860]
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.
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