title: Alpha-2-macroglobulin loaded microcapsules enhance human leukocyte functions and innate immune response.
abstract: Synthetic microstructures can be engineered to deliver bioactive compounds impacting on their pharmacokinetics and pharmacodynamics. Herein, we applied dextran-based layer-by-layer (LbL) microcapsules to deliver alpha-2-macroglobulin (α2MG), a protein with modulatory properties in inflammation. Extending recent observations made with dextran-microcapsules loaded with α2MG in experimental sepsis, we focused on the physical and chemical characteristics of these microstructures and determined their biology on rodent and human cells. We report an efficient encapsulation of α2MG into microcapsules, which enhanced i) human leukocyte recruitment to inflamed endothelium and ii) human macrophage phagocytosis: in both settings microcapsules were more effective than soluble α2MG or empty microcapsules (devoid of active protein). Translation of these findings revealed that intravenous administration of α2MG-microcapsules (but not empty microcapsules) promoted neutrophil migration into peritoneal exudates and augmented macrophage phagocytic functions, the latter response being associated with alteration of bioactive lipid mediators as assessed by mass spectrometry. The present study indicates that microencapsulation can be an effective strategy to harness the complex biology of α2MG with enhancing outcomes on fundamental processes of the innate immune response paving the way to potential future development in the control of sepsis.
authors.affiliation: William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, United Kingdom.
authors.forename: Donata
authors.initials: D
authors.lastname: Federici Canova
authors.affiliation: School of Engineering & Materials Science, Queen Mary University of London, London, United Kingdom; Saratov State University, Saratov, Russia.
authors.forename: Anton M
authors.initials: AM
authors.lastname: Pavlov
authors.affiliation: William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, United Kingdom.
authors.forename: Lucy V
authors.initials: LV
authors.lastname: Norling
authors.affiliation: William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, United Kingdom.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gobbetti
authors.affiliation: Department of Health Science, University of Eastern Piedmont, Novara, Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: Brunelleschi
authors.affiliation: MetaToul Lipidomics Facility, INSERM UMR1048, Toulouse, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Le Fauder
authors.affiliation: INSERM UMR1043, Université Toulouse III Paul-Sabatier, Toulouse, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Cenac
authors.affiliation: School of Engineering & Materials Science, Queen Mary University of London, London, United Kingdom.
authors.forename: Gleb B
authors.initials: GB
authors.lastname: Sukhorukov
authors.affiliation: William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, United Kingdom. Electronic address: m.perretti@qmul.ac.uk.
authors.forename: Mauro
authors.initials: M
authors.lastname: Perretti
mesh_terms: D000818:Animals; D002214:Capsules; D002478:Cells, Cultured; D003911:Dextrans / Q000737:chemistry; D004339:Drug Compounding; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D007962:Leukocytes / Q000187:drug effects* / Q000276:immunology; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D008297:Male; D008810:Mice, Inbred C57BL; D000511:alpha-Macroglobulins / Q000008:administration & dosage* / Q000494:pharmacology
chemical_list: C578813:A2M protein, human; D002214:Capsules; D003911:Dextrans; D000511:alpha-Macroglobulins
keywords: Alpha-2-macroglobulin; Inflammation; LbL microcapsules; Leukocyte activation; Phagocytosis