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Microparticle alpha-2-macroglobulin enhances pro-resolving responses and promotes survival in sepsis.


ABSTRACT: Incorporation 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.

SUBMITTER: Dalli J 

PROVIDER: S-EPMC3936490 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Microparticle alpha-2-macroglobulin enhances pro-resolving responses and promotes survival in sepsis.

Dalli Jesmond J   Norling Lucy V LV   Montero-Melendez Trinidad T   Federici Canova Donata D   Lashin Hazem H   Pavlov Anton M AM   Sukhorukov Gleb B GB   Hinds Charles J CJ   Perretti Mauro M  

EMBO molecular medicine 20131215 1


Incorporation 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 b  ...[more]

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