title: Sterile inflammation of endothelial cell-derived apoptotic bodies is mediated by interleukin-1α.
abstract: Sterile inflammation resulting from cell death is due to the release of cell contents normally inactive and sequestered within the cell; fragments of cell membranes from dying cells also contribute to sterile inflammation. Endothelial cells undergoing stress-induced apoptosis release membrane microparticles, which become vehicles for proinflammatory signals. Here, we show that stress-activated endothelial cells release two distinct populations of particles: One population consists of membrane microparticles (<1 μm, annexin V positive without DNA and no histones) and another larger (1-3 μm) apoptotic body-like particles containing nuclear fragments and histones, representing apoptotic bodies. Contrary to present concepts, endothelial microparticles do not contain IL-1α and do not induce neutrophilic chemokines in vitro. In contrast, the large apoptotic bodies contain the full-length IL-1α precursor and the processed mature form. In vitro, these apoptotic bodies induce monocyte chemotactic protein-1 and IL-8 chemokine secretion in an IL-1α-dependent but IL-1β-independent fashion. Injection of these apoptotic bodies into the peritoneal cavity of mice induces elevated serum neutrophil-inducing chemokines, which was prevented by cotreatment with the IL-1 receptor antagonist. Consistently, injection of these large apoptotic bodies into the peritoneal cavity induced a neutrophilic infiltration that was prevented by IL-1 blockade. Although apoptosis is ordinarily considered noninflammatory, these data demonstrate that nonphagocytosed endothelial apoptotic bodies are inflammatory, providing a vehicle for IL-1α and, therefore, constitute a unique mechanism for sterile inflammation.
authors.affiliation: Unité Mixte de Recherche 608, Aix-Marseille University, 13005 Marseille, France.
authors.forename: Yaël
authors.initials: Y
authors.lastname: Berda-Haddad
authors.forename: Stéphane
authors.initials: S
authors.lastname: Robert
authors.forename: Paul
authors.initials: P
authors.lastname: Salers
authors.forename: Leila
authors.initials: L
authors.lastname: Zekraoui
authors.forename: Catherine
authors.initials: C
authors.lastname: Farnarier
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
authors.forename: Françoise
authors.initials: F
authors.lastname: Dignat-George
authors.forename: Gilles
authors.initials: G
authors.lastname: Kaplanski
mesh_terms: D000818:Animals; D017209:Apoptosis; D015551:Autoimmunity; D055252:Cell-Derived Microparticles; D018932:Chemokine CCL2 / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology*; D006657:Histones / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007249:Inflammation; D053590:Interleukin 1 Receptor Antagonist Protein / Q000378:metabolism; D053582:Interleukin-1alpha / Q000378:metabolism*; D016209:Interleukin-8 / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015427:Reperfusion Injury / Q000473:pathology
chemical_list: D018932:Chemokine CCL2; D006657:Histones; D053590:Interleukin 1 Receptor Antagonist Protein; D053582:Interleukin-1alpha; D016209:Interleukin-8