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.
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