Inserm, Institut national de la santé et de la recherche médicale
Faculté de pharmacie, Aix Marseille Université

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Sterile inflammation of endothelial cell-derived apoptotic bodies is mediated by interleukin-1alpha

Y. Berda-Haddad, S. Robert, P. Salers, L. Zekraoui, C. Farnarier, CA. Dinarello, F. Dignat-George, G. Kaplanski. Proceedings of National Academy of Science USA, 2011 ; 108 : 20684-9.

RÉSUMÉ/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.