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

44 Scopus citations

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

Keywords

  • Apoptosis
  • Blood platelets
  • Granzyme B
  • Sepsis

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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    Freishtat, R. J., Natale, J. E., S.benton, A., Cohen, J., Sharron, M., Wiles, A. A., Ngor, W. M., Mojgani, B., Bradbury, M., Degnan, A., Sachdeva, R., Debiase, L. M., Ghimbovschi, S., Chow, M., Bunag, C., Kristosturyan, E., & Hoffman, E. P. (2009). Sepsis alters the megakaryocyte-platelet transcriptional axis resulting in granzyme B-mediated lymphotoxicity. American Journal of Respiratory and Critical Care Medicine, 179(6), 467-473. https://doi.org/10.1164/rccm.200807-1085OC