Sepsis promotes splenic production of a protective platelet pool with high CD40 ligand expression
Colin Valet, Mélia Magnen, Longhui Qiu, Simon J. Cleary, Kristin M. Wang, Serena Ranucci, Elodie Grockowiak, Rafik Boudra, Catharina Conrad, Yurim Seo, Daniel R. Calabrese, John R. Greenland, Andrew D. Leavitt, Emmanuelle Passegué, Simón Méndez-Ferrer, Filip K. Swirski, Mark R. Looney
Colin Valet, Mélia Magnen, Longhui Qiu, Simon J. Cleary, Kristin M. Wang, Serena Ranucci, Elodie Grockowiak, Rafik Boudra, Catharina Conrad, Yurim Seo, Daniel R. Calabrese, John R. Greenland, Andrew D. Leavitt, Emmanuelle Passegué, Simón Méndez-Ferrer, Filip K. Swirski, Mark R. Looney
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Research Article Hematology

Sepsis promotes splenic production of a protective platelet pool with high CD40 ligand expression

Abstract

Platelets have a wide range of functions including critical roles in hemostasis, thrombosis, and immunity. We hypothesized that during acute inflammation, such as in life-threatening sepsis, there are fundamental changes in the sites of platelet production and phenotypes of resultant platelets. Here, we showed during sepsis that the spleen was a major site of megakaryopoiesis and platelet production. Sepsis provoked an adrenergic-dependent mobilization of megakaryocyte-erythrocyte progenitors (MEPs) from the bone marrow to the spleen, where IL-3 induced their differentiation into megakaryocytes (MKs). In the spleen, immune-skewed MKs produced a CD40 ligandhi platelet population with potent immunomodulatory functions. Transfusions of post-sepsis platelets enriched from splenic production enhanced immune responses and reduced overall mortality in sepsis-challenged animals. These findings identify a spleen-derived protective platelet population that may be broadly immunomodulatory in acute inflammatory states such as sepsis.

Authors

Colin Valet, Mélia Magnen, Longhui Qiu, Simon J. Cleary, Kristin M. Wang, Serena Ranucci, Elodie Grockowiak, Rafik Boudra, Catharina Conrad, Yurim Seo, Daniel R. Calabrese, John R. Greenland, Andrew D. Leavitt, Emmanuelle Passegué, Simón Méndez-Ferrer, Filip K. Swirski, Mark R. Looney

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Figure 7

Transfusion of post-sepsis platelets confers protection against sepsis.

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Transfusion of post-sepsis platelets confers protection against sepsis. ...
(A) Schematic of septic mice transfused with platelets isolated on day 5 after saline or CS injection experiments. (B) Mean platelet counts, (C) bacterial CFU in the blood, (D) enumeration of neutrophils and Ly6Chi monocytes in the blood, (E) enumeration of neutrophil-platelet and Ly6Chi monocyte-platelet aggregates in the blood, (F) plasma TNF-α and IL-6 levels, (G) plasma AST levels, (H) BAL neutrophil count, (I) BAL protein levels, and (J) CitH3-DNA complexes (NETs) in the blood. n = 15–16 mice for all measurements. (K) Kaplan-Meier survival curve for mice transfused with 3 × 108 platelets on day 5 after saline or CS injection. n = 15 mice per group. Data indicate the mean ± SEM. *P < 0.05 and ***P < 0.0001, by 2-tailed, unpaired Student’s t test (B–J) and Gehan-Breslow-Wilcoxon test (K).