Sepsis alters the megakaryocyte-platelet transcriptional axis resulting in granzyme B-mediated lymphotoxicity

Robert J. Freishtat, JoAnne E Natale, Angela S.benton, Joanna Cohen, Matthew Sharron, Andrew A. Wiles, Wai Man Ngor, Bahar Mojgani, Margaret Bradbury, Andrew Degnan, Reecha Sachdeva, Lindsay M. Debiase, Svetlana Ghimbovschi, Matthew Chow, Clarice Bunag, Ervand Kristosturyan, Eric P. Hoffman

Research output: Contribution to journalArticle

39 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)467-473
Number of pages7
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume179
Issue number6
DOIs
StatePublished - Mar 15 2009

Fingerprint

Granzymes
Megakaryocytes
Sepsis
Blood Platelets
Apoptosis
Mortality
Microvessels
Inflammation
Messenger RNA

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 journalArticle

Freishtat, RJ, Natale, JE, S.benton, A, Cohen, J, Sharron, M, Wiles, AA, Ngor, WM, Mojgani, B, Bradbury, M, Degnan, A, Sachdeva, R, Debiase, LM, Ghimbovschi, S, Chow, M, Bunag, C, Kristosturyan, E & Hoffman, EP 2009, 'Sepsis alters the megakaryocyte-platelet transcriptional axis resulting in granzyme B-mediated lymphotoxicity', American Journal of Respiratory and Critical Care Medicine, vol. 179, no. 6, pp. 467-473. https://doi.org/10.1164/rccm.200807-1085OC
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. / Sepsis alters the megakaryocyte-platelet transcriptional axis resulting in granzyme B-mediated lymphotoxicity. In: American Journal of Respiratory and Critical Care Medicine. 2009 ; Vol. 179, No. 6. pp. 467-473.
@article{4ef04ff1c3cf4ff29c33eb34f1edb77d,
title = "Sepsis alters the megakaryocyte-platelet transcriptional axis resulting in granzyme B-mediated lymphotoxicity",
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.",
keywords = "Apoptosis, Blood platelets, Granzyme B, Sepsis",
author = "Freishtat, {Robert J.} and Natale, {JoAnne E} and Angela S.benton and Joanna Cohen and Matthew Sharron and Wiles, {Andrew A.} and Ngor, {Wai Man} and Bahar Mojgani and Margaret Bradbury and Andrew Degnan and Reecha Sachdeva and Debiase, {Lindsay M.} and Svetlana Ghimbovschi and Matthew Chow and Clarice Bunag and Ervand Kristosturyan and Hoffman, {Eric P.}",
year = "2009",
month = "3",
day = "15",
doi = "10.1164/rccm.200807-1085OC",
language = "English (US)",
volume = "179",
pages = "467--473",
journal = "American Journal of Respiratory and Critical Care Medicine",
issn = "1073-449X",
publisher = "American Thoracic Society",
number = "6",

}

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 -