Enhanced dendritic cell survival attenuates lipopolysaccharide-induced immunosuppression and increases resistance to lethal endotoxic shock.
Impaired immune function and associated immunosuppression are hallmarks of septic syndromes. As part of an overall deactivation of the immune system, profound depletion of dendritic cells (DCs) occurs in both septic patients and septic mice. Such depletion of DCs is potentially associated with immunosuppression and with failure to induce a protective Th1 immune response; it may equally be predictive of fatal outcome in septic patients. To evaluate the impact of enhanced DC survival on LPS-induced immunosuppression and on survival after LPS-induced septic shock, we created a transgenic mouse model specifically overexpressing the human form of the antiapoptotic protein Bcl-2 in DCs (DC-hBcl-2 mice). DCs derived from DC-hBcl-2 mice exhibited higher resistance to maturation-induced apoptosis after LPS treatment both in vitro and in vivo. Moreover, prolongation of DC survival diminished sublethal LPS-induced DC loss and immunosuppression, with maintenance of the differentiation potential of Th1 cells and enhanced T cell activation. Such modulation of the immune response appears to constitute a key feature of the attenuated mortality observed after LPS-induced shock in DC-hBcl-2 mice. Our study therefore identifies DC death as a key determinant of endotoxin-induced immunosuppression and mortality in mice.
Gautier
Emmanuel L
EL
Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche S551, Dyslipoproteinemia and Atherosclerosis Research Unit, Hôpital de la Pitié, Paris, France.
Huby
Thierry
T
Saint-Charles
Flora
F
Ouzilleau
Betty
B
Chapman
M John
MJ
Lesnik
Philippe
P
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D002470:Cell Survival; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D015870:Gene Expression; D006801:Humans; D007108:Immune Tolerance; D008070:Lipopolysaccharides / Q000633:toxicity*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D012772:Shock, Septic / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology
D016207:Cytokines; D008070:Lipopolysaccharides; D019253:Proto-Oncogene Proteins c-bcl-2