Megakaryocyte emperipolesis arms neutrophils via intracellular provisioning

Abstract

Neutrophils are phenotypically heterogenous cells that mediate host defense and tissue homeostasis. Here, we identify emperipolesis - the evolutionarily conserved process by which neutrophils pass through megakaryocytes - as a phenotypically transformative route of egress from bone marrow. By intravital microscopy and 3-D histology, we show that the rapid form emperipolesis is markedly enhanced under inflammatory conditions. Neutrophils exit from megakaryocytes directly to the blood, acquiring exosomes enriched in proteins related to metabolism, migration, and immune function. This transfer induces a distinct neutrophil phenotype characterized by enhanced glycolysis, oxidative phosphorylation, cytokine release, and longevity. Correspondingly, emperipolesis-educated neutrophils display accelerated migration in vitro and in vivo. Disrupting emperipolesis does not alter circulating neutrophil abundance but impairs neutrophil infiltration into inflamed tissues, including Pseudomonas aeruginosa-infected lung. These findings establish emperipolesis as a mechanism by which megakaryocytes amplify neutrophil-mediated immunity.