Abstract
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 lym- phoid 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 467-473 |
| Number of pages | 7 |
| Journal | American Journal of Respiratory and Critical Care Medicine |
| Volume | 179 |
| Issue number | 6 |
| DOIs | |
| State | Published - Mar 15 2009 |
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Keywords
- Apoptosis
- Blood platelets
- Granzyme B
- Sepsis
ASJC Scopus subject areas
- Pulmonary and Respiratory Medicine
- Critical Care and Intensive Care Medicine
Cite this
Sepsis alters the megakaryocyte-platelet transcriptional axis resulting in granzyme B-mediated lymphotoxicity. / Freishtat, Robert J.; Natale, JoAnne E; S.benton, Angela; Cohen, Joanna; Sharron, Matthew; Wiles, Andrew A.; Ngor, Wai Man; Mojgani, Bahar; Bradbury, Margaret; Degnan, Andrew; Sachdeva, Reecha; Debiase, Lindsay M.; Ghimbovschi, Svetlana; Chow, Matthew; Bunag, Clarice; Kristosturyan, Ervand; Hoffman, Eric P.
In: American Journal of Respiratory and Critical Care Medicine, Vol. 179, No. 6, 15.03.2009, p. 467-473.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Sepsis alters the megakaryocyte-platelet transcriptional axis resulting in granzyme B-mediated lymphotoxicity
AU - Freishtat, Robert J.
AU - Natale, JoAnne E
AU - S.benton, Angela
AU - Cohen, Joanna
AU - Sharron, Matthew
AU - Wiles, Andrew A.
AU - Ngor, Wai Man
AU - Mojgani, Bahar
AU - Bradbury, Margaret
AU - Degnan, Andrew
AU - Sachdeva, Reecha
AU - Debiase, Lindsay M.
AU - Ghimbovschi, Svetlana
AU - Chow, Matthew
AU - Bunag, Clarice
AU - Kristosturyan, Ervand
AU - Hoffman, Eric P.
PY - 2009/3/15
Y1 - 2009/3/15
N2 - 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 lym- phoid 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.
AB - 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 lym- phoid 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.
KW - Apoptosis
KW - Blood platelets
KW - Granzyme B
KW - Sepsis
UR - http://www.scopus.com/inward/record.url?scp=63249101191&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=63249101191&partnerID=8YFLogxK
U2 - 10.1164/rccm.200807-1085OC
DO - 10.1164/rccm.200807-1085OC
M3 - Article
C2 - 19136373
AN - SCOPUS:63249101191
VL - 179
SP - 467
EP - 473
JO - American Journal of Respiratory and Critical Care Medicine
JF - American Journal of Respiratory and Critical Care Medicine
SN - 1073-449X
IS - 6
ER -