title: CD95 engagement induces disseminated endothelial cell apoptosis in vivo: immunopathologic implications.
abstract: Fas (CD95) is a death receptor involved in apoptosis induction on engagement by Fas ligand (CD95L). Although CD95L-mediated apoptosis has been proposed as a pathogenic mechanism in a wide range of diseases, including graft-versus-host disease, systemic CD95 engagement in mice by agonistic CD95-specific antibodies or by soluble multimeric CD95L (smCD95L), though lethal, has been reported to cause apoptosis only in a limited range of cell types, that is, hepatocytes, hepatic sinusoidal endothelial cells, and lymphocytes. Another member of the tumor necrosis factor (TNF)/CD95L family, TNF-alpha, induces disseminated vascular endothelial cell apoptosis, which precedes apoptosis of other cell types and lethal multiorgan failure. Here we show that systemic CD95 engagement in vivo by agonistic CD95-specific antibody or smCD95L causes rapid, extensive, and disseminated endothelial cell apoptosis throughout the body, by a mechanism that does not depend on TNF-alpha. Disseminated endothelial cell apoptosis was also the first detectable lesion in a murine model of acute tissue damage induced by systemic transfer of allogeneic lymphocytes and did not occur when allogeneic lymphocytes were from CD95L-defective mice. Both vascular and additional tissue lesions induced by agonistic CD95-specific antibody, smCD95L, or allogeneic lymphocytes were prevented by treatment with an inhibitor of caspase-8, the upstream caspase coupled to CD95 death signaling. Vascular lesions are likely to play an important role in the pathogenesis of allogeneic immune responses and of other diseases involving circulating CD95L-expressing cells or smCD95L, and the prevention of CD95-mediated death signaling in endothelial cells may have therapeutic implications in these diseases.
authors.affiliation: EMI-U 9922 INSERM/Université Paris 7, IFR 02, Hôpital Bichat-Claude Bernard, AP-HP, 75877 Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Janin
authors.forename: Christophe
authors.initials: C
authors.lastname: Deschaumes
authors.forename: Marjan
authors.initials: M
authors.lastname: Daneshpouy
authors.forename: Jérôme
authors.initials: J
authors.lastname: Estaquier
authors.forename: Juliette
authors.initials: J
authors.lastname: Micic-Polianski
authors.forename: Premavathy
authors.initials: P
authors.lastname: Rajagopalan-Levasseur
authors.forename: Khadija
authors.initials: K
authors.lastname: Akarid
authors.forename: Nicolas
authors.initials: N
authors.lastname: Mounier
authors.forename: Eliane
authors.initials: E
authors.lastname: Gluckman
authors.forename: Gérard
authors.initials: G
authors.lastname: Socié
authors.forename: Jean Claude
authors.initials: JC
authors.lastname: Ameisen
mesh_terms: D000818:Animals; D000906:Antibodies; D017209:Apoptosis / Q000187:drug effects*; D001921:Brain / Q000098:blood supply / Q000473:pathology; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000473:pathology*; D020287:In Situ Nick-End Labeling; D007668:Kidney / Q000098:blood supply / Q000473:pathology; D008024:Ligands; D008099:Liver / Q000098:blood supply / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008854:Microscopy, Electron; D009206:Myocardium / Q000473:pathology; D011485:Protein Binding; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor / Q000276:immunology / Q000378:metabolism / Q000502:physiology*
chemical_list: D000906:Antibodies; D008024:Ligands; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; C505526:Casp8 protein, mouse; C506434:Casp9 protein, mouse; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases