Dalli, Jesmond PNorling, Lucy VMontero-Melendez, TrinidadCanova, Donata FedericiLashin, HazemPavlov, Anton MSukhorukov, Gleb BHinds, Charles JPerretti, Mauro2014-04-112014Dalli, Jesmond, Lucy V Norling, Trinidad Montero-Melendez, Donata Federici Canova, Hazem Lashin, Anton M Pavlov, Gleb B Sukhorukov, Charles J Hinds, and Mauro Perretti. 2014. “Microparticle alpha-2-macroglobulin enhances pro-resolving responses and promotes survival in sepsis.” EMBO Molecular Medicine 6 (1): 27-42. doi:10.1002/emmm.201303503. http://dx.doi.org/10.1002/emmm.201303503.1757-4676http://nrs.harvard.edu/urn-3:HUL.InstRepos:12064533Incorporation of locally produced signaling molecules into cell-derived vesicles may serve as an endogenous mediator delivery system. We recently reported that levels alpha-2-macroglobulin (A2MG)-containing microparticles are elevated in plasma from patients with sepsis. Herein, we investigated the immunomodulatory actions of A2MG containing microparticles during sepsis. Administration of A2MG-enriched (A2MG-E)-microparticles to mice with microbial sepsis protected against hypothermia, reduced bacterial titers, elevated immunoresolvent lipid mediator levels in inflammatory exudates and reduced systemic inflammation. A2MG-E microparticles also enhanced survival in murine sepsis, an action lost in mice transfected with siRNA for LRP1, a putative A2MG receptor. In vitro, A2MG was functionally transferred onto endothelial cell plasma membranes from microparticles, augmenting neutrophil–endothelial adhesion. A2MG also modulated human leukocyte responses: enhanced bacterial phagocytosis, reactive oxygen species production, cathelicidin release, prevented endotoxin induced CXCR2 downregulation and preserved neutrophil chemotaxis in the presence of LPS. A significant association was also found between elevated plasma levels of A2MG-containing microparticles and survival in human sepsis patients. Taken together, these results identify A2MG enrichment in microparticles as an important host protective mechanism in sepsis.en-USactivationinnate immunitylipoprotein receptor-related protein 1neutrophilphagocytosisJournal Article2014-04-1110.1002/emmm.201303503