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

Am J Respir Crit Care Med. 2009 Mar 15;179(6):467-73. doi: 10.1164/rccm.200807-1085OC. Epub 2009 Jan 8.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Animals
  • Apoptosis*
  • Blood Platelets / metabolism*
  • Child
  • Child, Preschool
  • Female
  • Granzymes / genetics
  • Granzymes / metabolism*
  • Humans
  • Infant
  • Male
  • Megakaryocytes / metabolism
  • Mice
  • RNA, Messenger / metabolism
  • Sepsis / genetics
  • Sepsis / metabolism*
  • Sepsis / pathology
  • Severity of Illness Index
  • Spleen / pathology*


  • RNA, Messenger
  • GZMB protein, human
  • Granzymes
  • GZMA protein, human