Journal
EMBO MOLECULAR MEDICINE
Volume 6, Issue 1, Pages 27-42Publisher
WILEY
DOI: 10.1002/emmm.201303503
Keywords
phagocytosis; activation; lipoprotein receptor-related protein 1; neutrophil; innate immunity
Categories
Funding
- Wellcome Trust [086867/Z/08]
- William Harvey Research Foundation
- United Kingdom Intensive Care Society
- National Institutes of Health GM [P01GM095967]
- Arthritis Research UK Career Development Fellowship [19909]
- EPSRC Seed Funding Cross disciplinary Grant (QMUL)
- Versus Arthritis [19909] Funding Source: researchfish
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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.
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