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

35 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

Fingerprint

alpha-Macroglobulins
Sepsis
Survival
Cell-Derived Microparticles
Neutrophils
Low Density Lipoprotein Receptor-Related Protein-1
Exudates and Transudates
Chemotaxis
Hypothermia
Phagocytosis
Endotoxins
Small Interfering RNA
Reactive Oxygen Species
Leukocytes
Down-Regulation
Endothelial Cells
Cell Membrane
Inflammation
Lipids

Keywords

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

ASJC Scopus subject areas

  • Molecular Medicine

Cite this

Dalli, J., Norling, L. V., Montero-Melendez, T., Canova, D. F., Lashin, H., Pavlov, A. M., ... 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

Microparticle alpha-2-macroglobulin enhances pro-resolving responses and promotes survival in sepsis. / Dalli, Jesmond; Norling, Lucy V.; Montero-Melendez, Trinidad; Canova, Donata Federici; Lashin, Hazem; Pavlov, Anton M.; Sukhorukov, Gleb B.; Hinds, Charles J.; Perretti, Mauro.

In: EMBO Molecular Medicine, Vol. 6, No. 1, 01.2014, p. 27-42.

Research output: Contribution to journalArticle

Dalli, J, Norling, LV, Montero-Melendez, T, Canova, DF, Lashin, H, Pavlov, AM, Sukhorukov, GB, Hinds, CJ & Perretti, M 2014, 'Microparticle alpha-2-macroglobulin enhances pro-resolving responses and promotes survival in sepsis', EMBO Molecular Medicine, vol. 6, no. 1, pp. 27-42. https://doi.org/10.1002/emmm.201303503
Dalli, Jesmond ; Norling, Lucy V. ; Montero-Melendez, Trinidad ; Canova, Donata Federici ; Lashin, Hazem ; Pavlov, Anton M. ; Sukhorukov, Gleb B. ; Hinds, Charles J. ; Perretti, Mauro. / Microparticle alpha-2-macroglobulin enhances pro-resolving responses and promotes survival in sepsis. In: EMBO Molecular Medicine. 2014 ; Vol. 6, No. 1. pp. 27-42.
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