title: Endotoxin-induced monocytic microparticles have contrasting effects on endothelial inflammatory responses.
abstract: Septic shock is a severe disease state characterised by the body's life threatening response to infection. Complex interactions between endothelial cells and circulating monocytes are responsible for microvasculature dysfunction contributing to the pathogenesis of this syndrome. Here, we intended to determine whether microparticles derived from activated monocytes contribute towards inflammatory processes and notably vascular permeability. We found that endotoxin stimulation of human monocytes enhances the release of microparticles of varying phenotypes and mRNA contents. Elevated numbers of LPS-induced monocytic microparticles (mMP) expressed CD54 and contained higher levels of transcripts for pro-inflammatory cytokines such as TNF, IL-6 and IL-8. Using a prothrombin time assay, a greater reduction in plasma coagulation time was observed with LPS-induced mMP than with non-stimulated mMP. Co-incubation of mMP with the human brain endothelial cell line hCMEC/D3 triggered their time-dependent uptake and significantly enhanced endothelial microparticle release. Unexpectedly, mMP also modified signalling pathways by diminishing pSrc (tyr416) expression and promoted endothelial monolayer tightness, as demonstrated by endothelial impedance and permeability assays. Altogether, these data strongly suggest that LPS-induced mMP have contrasting effects on the intercellular communication network and display a dual potential: enhanced pro-inflammatory and procoagulant properties, together with protective function of the endothelium.
authors.affiliation: Vascular Immunology Unit, Sydney Medical School & Bosch Institute, University of Sydney, Camperdown, Australia.
authors.forename: Beryl
authors.initials: B
authors.lastname: Wen
authors.affiliation: Vascular Immunology Unit, Sydney Medical School & Bosch Institute, University of Sydney, Camperdown, Australia.
authors.forename: Valery
authors.initials: V
authors.lastname: Combes
authors.affiliation: Vascular Immunology Unit, Sydney Medical School & Bosch Institute, University of Sydney, Camperdown, Australia.
authors.forename: Amandine
authors.initials: A
authors.lastname: Bonhoure
authors.affiliation: Weill Medical College, Cornell University, New York, New York, United States of America.
authors.forename: Babette B
authors.initials: BB
authors.lastname: Weksler
authors.affiliation: Institut Cochin, INSERM U1016, Paris, France; CNRS, UMR 8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Pierre-Olivier
authors.initials: PO
authors.lastname: Couraud
authors.affiliation: Vascular Immunology Unit, Sydney Medical School & Bosch Institute, University of Sydney, Camperdown, Australia.
authors.forename: Georges E R
authors.initials: GE
authors.lastname: Grau
mesh_terms: D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D055252:Cell-Derived Microparticles / Q000737:chemistry* / Q000378:metabolism; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; D016209:Interleukin-8; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1