Sepsis alters the megakaryocyte-platelet transcriptional axis resulting in granzyme B-mediated lymphotoxicity.
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.
Freishtat
Robert J
RJ
Division of Emergency Medicine, Children's National Medical Center, 111 Michigan Avenue NW, Washington, DC 20010, USA. rfreishtat@cnmcresearch.org
Natale
Joanne
J
Benton
Angela S
AS
Cohen
Joanna
J
Sharron
Matthew
M
Wiles
Andrew A
AA
Ngor
Wai-Man
WM
Mojgani
Bahar
B
Bradbury
Margaret
M
Degnan
Andrew
A
Sachdeva
Reecha
R
Debiase
Lindsay M
LM
Ghimbovschi
Svetlana
S
Chow
Matthew
M
Bunag
Clarice
C
Kristosturyan
Ervand
E
Hoffman
Eric P
EP
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*
D012333:RNA, Messenger; C509213:GZMB protein, human; D053804:Granzymes; C509212:GZMA protein, human