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Sepsis Alters the Megakaryocyte–Platelet Transcriptional Axis Resulting in Granzyme B–mediated Lymphotoxicity

¹ Division of Emergency Medicine, Department of Pediatrics and ² Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC; ³ George Washington University School of Medicine and Health Sciences, Washington, DC; ⁴ Division of Critical Care Medicine, Department of Pediatrics, and ⁵ School of Medicine, University of California at Davis Medical Center, Sacramento, California; ⁶ Division of Critical Care Medicine, Children's National Medical Center, Washington, DC; ⁷ University of California at Davis, Davis, California; ⁸ George Washington University, Washington, DC

Correspondence and requests for reprints should be addressed to Robert J. Freishtat, M.D., M.P.H., Division of Emergency Medicine, Children's National Medical Center, 111 Michigan Avenue NW, Washington, DC 20010. E-mail: rfreishtat{at}cnmcresearch.org

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.

Key Words: blood platelets • sepsis • granzyme B • apoptosis

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject No studies have shown acute changes in platelet mRNA pools as a function of a systemic stimulus, such as experimental or clinical sepsis. What This Study Adds to the Field We determined that sepsis induces changes in the megakaryocyte-platelet transcriptional axis and show that the resulting platelets are strongly lymphotoxic. In addition, using platelets from a murine-induced sepsis model, we identified the potent cytotoxic serine protease, granzyme B, as the cause of this lymphotoxicity.