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

Jesmond Dalli, Lucy V. Norling, Trinidad Montero-Melendez, Donata Federici Canova, Hazem Lashin, Anton M. Pavlov, Gleb B. Sukhorukov, Charles J. Hinds, Mauro Perretti

Research output: Contribution to journalArticle

37 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)27-42
Number of pages16
JournalEMBO Molecular Medicine
Volume6
Issue number1
DOIs
Publication statusPublished - Jan 2014
Externally publishedYes

Keywords

  • Activation
  • Innate immunity
  • Lipoprotein receptor-related protein 1
  • Neutrophil
  • Phagocytosis

ASJC Scopus subject areas

  • Molecular Medicine

Fingerprint Dive into the research topics of 'Microparticle alpha-2-macroglobulin enhances pro-resolving responses and promotes survival in sepsis'. Together they form a unique fingerprint.

  • Cite this

    Dalli, J., Norling, L. V., Montero-Melendez, T., Canova, D. F., Lashin, H., Pavlov, A. M., Sukhorukov, G. B., Hinds, C. J., & Perretti, M. (2014). Microparticle alpha-2-macroglobulin enhances pro-resolving responses and promotes survival in sepsis. EMBO Molecular Medicine, 6(1), 27-42. https://doi.org/10.1002/emmm.201303503