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

EMBO Mol Med. 2014 Jan;6(1):27-42. doi: 10.1002/emmm.201303503. Epub 2013 Dec 15.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimicrobial Cationic Peptides / metabolism
  • Cell Membrane / metabolism
  • Cytoplasmic Vesicles / metabolism
  • Cytoplasmic Vesicles / microbiology
  • Escherichia coli / physiology
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Inflammation / metabolism
  • Inflammation / pathology
  • Kaplan-Meier Estimate
  • Leukocytes / immunology
  • Leukocytes / metabolism
  • Lipopolysaccharides / toxicity
  • Male
  • Mice
  • Microspheres*
  • Neutrophils / cytology
  • Neutrophils / drug effects
  • Neutrophils / immunology
  • Phagocytosis
  • Reactive Oxygen Species / metabolism
  • Receptors, Interleukin-8B / metabolism
  • Sepsis / mortality*
  • Sepsis / prevention & control*
  • alpha-Macroglobulins / metabolism
  • alpha-Macroglobulins / pharmacology*

Substances

  • Antimicrobial Cationic Peptides
  • Lipopolysaccharides
  • Reactive Oxygen Species
  • Receptors, Interleukin-8B
  • alpha-Macroglobulins
  • CAP18 lipopolysaccharide-binding protein