title: A20 expression in dendritic cells protects mice from LPS-induced mortality.
abstract: DCs contribute to immune homeostasis under physiological conditions and regulate the immune activation during infection. The deubiquitinase A20 inhibits the activation of NF-κB-dependent immune reactions, and prevents the hyperactivation of DCs under steady-state conditions. However, the role of DC-specific A20 under pathological conditions is unknown. Here, we demonstrate that upon injection of low-dose LPS, mice with DC-specific A20 deletion (CD11c-Cre A20(fl/fl) ) died within 6 h, whereas A20(fl/fl) controls survived. LPS-induced mortality in CD11c-Cre A20(fl/fl) mice was characterized by increased serum levels of IL-2, IL-10, IL-12, IFN-γ, and TNF. Upon LPS stimulation, the activation of NF-κB and ERK-NFATc3 pathways were enhanced in A20-deficient DCs, resulting in an increased production of IL-2, IL-12, and TNF both in vitro and in vivo. Targeted inhibition of ERK in A20-deficient DCs abolished the increased production of IL-2. A20-deficient DCs failed to induce LPS tolerance, which was independent of T cells and the intestinal flora, since T-cell depletion and decolonization of CD11c-Cre A20(fl/fl) mice could not prevent death of LPS-challenged CD11c-Cre A20(fl/fl) mice. In conclusion, these findings show that DC-specific A20 preserves immune homeostasis in steady-state conditions and is also required for LPS tolerance.
authors.affiliation: Institute of Medical Microbiology and Hospital Hygiene, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.
authors.forename: Nguyen Thi
authors.initials: NT
authors.lastname: Xuan
authors.forename: Xu
authors.initials: X
authors.lastname: Wang
authors.forename: Gopala
authors.initials: G
authors.lastname: Nishanth
authors.forename: Ari
authors.initials: A
authors.lastname: Waisman
authors.forename: Katrin
authors.initials: K
authors.lastname: Borucki
authors.forename: Berend
authors.initials: B
authors.lastname: Isermann
authors.forename: Michael
authors.initials: M
authors.lastname: Naumann
authors.forename: Martina
authors.initials: M
authors.lastname: Deckert
authors.forename: Dirk
authors.initials: D
authors.lastname: Schlüter
mesh_terms: D000818:Animals; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000276:immunology*; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology*; D008070:Lipopolysaccharides / Q000633:toxicity*; D051379:Mice; D008822:Mice, Transgenic; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
chemical_list: D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D048049:Extracellular Signal-Regulated MAP Kinases; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D003546:Cysteine Endopeptidases; C513261:Tnfaip3 protein, mouse
keywords: A20; Autoimmunity; DC; LPS tolerance; Mice