title: Toll-like receptors 2 and 4 contribute to sepsis-induced depletion of spleen dendritic cells.
abstract: Depletion of dendritic cells (DC) in secondary lymphoid organs is a hallmark of sepsis-induced immune dysfunction. In this setting, we investigated if Toll-like receptor (TLR)-dependent signaling might modulate the maturation process and the survival of DC. Using a model of sublethal polymicrobial sepsis induced by cecal ligation and puncture, we investigated the quantitative and functional features of spleen DC in wild-type, TLR2(-/-), TLR4(-/-), and TLR2(-/-) TLR4(-/-) mice. By 24 h, a decrease in the relative percentage of CD11c(high) spleen DC occurred in wild-type mice but was prevented in TLR2(-/-), TLR4(-/-), and TLR2(-/-) TLR4(-/-) mice. In wild-type mice, sepsis dramatically affected both CD11c(+) CD8alpha(+) and CD11c(+) CD8alpha(-) subsets. In all three types of knockout mice studied, the CD11c(+) CD8alpha(+) subset followed a depletion pattern similar to that for wild-type mice. In contrast, the loss of CD11c(+) CD8alpha(-) cells was attenuated in TLR2(-/-) and TLR4(-/-) mice and completely prevented in TLR2(-/-) TLR4(-/-) mice. Accordingly, apoptosis of spleen DC was increased in septic wild-type mice and inhibited in knockout mice. In addition we characterized the functional features of spleen DC obtained from septic mice. As shown by increased expression of major histocompatibility complex class II and CD86, polymicrobial sepsis induced maturation of DC, with subsequent increased capacity to prime T lymphocytes, similarly in wild-type and knockout mice. In response to CpG DNA stimulation, production of interleukin-12 was equally impaired in DC obtained from wild-type and knockout septic mice. In conclusion, although dispensable for the DC maturation process, TLR2 and TLR4 are involved in the mechanisms leading to depletion of spleen DC following polymicrobial sepsis.
authors.affiliation: Département de Biologie Cellulaire, Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Pène
authors.forename: Emilie
authors.initials: E
authors.lastname: Courtine
authors.forename: Fatah
authors.initials: F
authors.lastname: Ouaaz
authors.forename: Benjamin
authors.initials: B
authors.lastname: Zuber
authors.forename: Bertrand
authors.initials: B
authors.lastname: Sauneuf
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Sirgo
authors.forename: Christophe
authors.initials: C
authors.lastname: Rousseau
authors.forename: Julie
authors.initials: J
authors.lastname: Toubiana
authors.forename: Viviane
authors.initials: V
authors.lastname: Balloy
authors.forename: Michel
authors.initials: M
authors.lastname: Chignard
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Mira
authors.forename: Jean-Daniel
authors.initials: JD
authors.lastname: Chiche
mesh_terms: D000818:Animals; D017209:Apoptosis; D051940:B7-2 Antigen / Q000096:biosynthesis; D018845:CD11 Antigens / Q000032:analysis; D016827:CD8 Antigens / Q000032:analysis; D003713:Dendritic Cells / Q000737:chemistry / Q000276:immunology*; D005260:Female; D020869:Gene Expression Profiling; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018805:Sepsis / Q000276:immunology*; D013154:Spleen / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000276:immunology*
chemical_list: D051940:B7-2 Antigen; D018845:CD11 Antigens; D016827:CD8 Antigens; C409469:CD8 antigen, alpha chain; D000949:Histocompatibility Antigens Class II; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4