title: 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.
authors.affiliation: Centre for Biochemical Pharmacology The William Harvey Research Institute, Barts and The London School of Medicine Queen Mary University of London, London, UK.
authors.forename: Jesmond
authors.initials: J
authors.lastname: Dalli
authors.forename: Lucy V
authors.initials: LV
authors.lastname: Norling
authors.forename: Trinidad
authors.initials: T
authors.lastname: Montero-Melendez
authors.forename: Donata
authors.initials: D
authors.lastname: Federici Canova
authors.forename: Hazem
authors.initials: H
authors.lastname: Lashin
authors.forename: Anton M
authors.initials: AM
authors.lastname: Pavlov
authors.forename: Gleb B
authors.initials: GB
authors.lastname: Sukhorukov
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Hinds
authors.forename: Mauro
authors.initials: M
authors.lastname: Perretti
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D022162:Cytoplasmic Vesicles / Q000378:metabolism / Q000382:microbiology; D004926:Escherichia coli / Q000502:physiology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D053208:Kaplan-Meier Estimate; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D008863:Microspheres; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D010587:Phagocytosis; D017382:Reactive Oxygen Species / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000378:metabolism; D018805:Sepsis / Q000401:mortality* / Q000517:prevention & control*; D000511:alpha-Macroglobulins / Q000378:metabolism / Q000494:pharmacology*; D054804:Cathelicidins
chemical_list: D023181:Antimicrobial Cationic Peptides; D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; D023063:Receptors, Interleukin-8B; D000511:alpha-Macroglobulins; D054804:Cathelicidins