Sepsis Alters the Megakaryocyte-Platelet Transcriptional Axis Resulting in Granzyme B-mediated Lymphotoxicity

被引:56
作者
Freishtat, Robert J. [1 ,2 ,3 ]
Natale, JoAnne [4 ,5 ]
Benton, Angela S. [2 ]
Cohen, Joanna [1 ,3 ]
Sharron, Matthew [6 ]
Wiles, Andrew A. [2 ]
Ngor, Wai-Man [2 ]
Mojgani, Bahar [2 ]
Bradbury, Margaret [2 ]
Degnan, Andrew [3 ]
Sachdeva, Reecha [3 ]
DeBiase, Lindsay M. [2 ]
Ghimbovschi, Svetlana [2 ]
Chow, Matthew [7 ]
Bunag, Clarice [7 ]
Kristosturyan, Ervand
Hoffman, Eric P. [2 ,3 ]
机构
[1] Childrens Natl Med Ctr, Div Emergency Med, Dept Pediat, Washington, DC 20010 USA
[2] Childrens Natl Med Ctr, Med Genet Res Ctr, Washington, DC 20010 USA
[3] George Washington Univ, Sch Med & Hlth Sci, Washington, DC 20052 USA
[4] Univ Calif Davis, Med Ctr, Div Crit Care Med, Dept Pediat, Sacramento, CA 95817 USA
[5] Univ Calif Davis, Med Ctr, Sch Med, Sacramento, CA 95817 USA
[6] Childrens Natl Med Ctr, Div Crit Care Med, Washington, DC 20010 USA
[7] Univ Calif Davis, Davis, CA 95616 USA
基金
美国国家卫生研究院;
关键词
blood platelets; sepsis; granzyme B; apoptosis; CELL APOPTOSIS; ESCHERICHIA-COLI; SEPTIC SHOCK; CUTTING EDGE; DEATH; EXPRESSION; PERFORIN; LYMPHOCYTE; ACTIVATION; EPIDEMIOLOGY;
D O I
10.1164/rccm.200807-1085OC
中图分类号
R4 [临床医学];
学科分类号
1002 ; 100602 ;
摘要
Rationale: Sepsis-related mortality results in part from immunodeficiency secondary to profound lymphoid apoptosis. The biological mechanisms responsible are not understood. Objectives: Because recent evidence shows that platelets are involved in microvascular inflammation and that they accumulate in lymphoid microvasculature in sepsis, we hypothesized a direct role for platelets in sepsis-related lymphoid apoptosis. Methods: We studied megakaryocytes and platelets from a murine-induced sepsis model, with validation in septic children, which showed induction of the cytotoxic serine protease granzyme B. Measurements and Main Results: Platelets from septic mice induced marked apoptosis of healthy splenocytes ex vivo. Platelets from septic granzyme B null (-/-) mice showed no lymphotoxicity. Conclusions: Our findings establish a conceptual advance in sepsis: Septic megakaryocytes produce platelets with acutely altered mRNA profiles, and these platelets mediate lymphotoxicity via granzyme B. Given the contribution of lymphoid apoptosis to sepsis-related mortality, modulation of platelet granzyme B becomes an important new target for investigation and therapy.
引用
收藏
页码:467 / 473
页数:7
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