title: Sepsis alters the megakaryocyte-platelet transcriptional axis resulting in granzyme B-mediated lymphotoxicity.
abstract: BACKGROUND
  Sepsis-related mortality results in part from immunodeficiency secondary to profound lymphoid apoptosis. The biological mechanisms responsible are not understood.
  
  
  OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Division of Emergency Medicine, Children's National Medical Center, 111 Michigan Avenue NW, Washington, DC 20010, USA. rfreishtat@cnmcresearch.org
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Freishtat
authors.forename: Joanne
authors.initials: J
authors.lastname: Natale
authors.forename: Angela S
authors.initials: AS
authors.lastname: Benton
authors.forename: Joanna
authors.initials: J
authors.lastname: Cohen
authors.forename: Matthew
authors.initials: M
authors.lastname: Sharron
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Wiles
authors.forename: Wai-Man
authors.initials: WM
authors.lastname: Ngor
authors.forename: Bahar
authors.initials: B
authors.lastname: Mojgani
authors.forename: Margaret
authors.initials: M
authors.lastname: Bradbury
authors.forename: Andrew
authors.initials: A
authors.lastname: Degnan
authors.forename: Reecha
authors.initials: R
authors.lastname: Sachdeva
authors.forename: Lindsay M
authors.initials: LM
authors.lastname: Debiase
authors.forename: Svetlana
authors.initials: S
authors.lastname: Ghimbovschi
authors.forename: Matthew
authors.initials: M
authors.lastname: Chow
authors.forename: Clarice
authors.initials: C
authors.lastname: Bunag
authors.forename: Ervand
authors.initials: E
authors.lastname: Kristosturyan
authors.forename: Eric P
authors.initials: EP
authors.lastname: Hoffman
mesh_terms: D000293:Adolescent; D000818:Animals; D017209:Apoptosis; D001792:Blood Platelets / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D005260:Female; D053804:Granzymes / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007223:Infant; D008297:Male; D008533:Megakaryocytes / Q000378:metabolism; D051379:Mice; D012333:RNA, Messenger / Q000378:metabolism; D018805:Sepsis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012720:Severity of Illness Index; D013154:Spleen / Q000473:pathology*
chemical_list: D012333:RNA, Messenger; C509213:GZMB protein, human; D053804:Granzymes; C509212:GZMA protein, human