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. 2015 Mar;45(3):818-28.
doi: 10.1002/eji.201444795. Epub 2014 Dec 28.

A20 expression in dendritic cells protects mice from LPS-induced mortality

Nguyen Thi Xuan  1 , Xu Wang, Gopala Nishanth, Ari Waisman, Katrin Borucki, Berend Isermann, Michael Naumann, Martina Deckert, Dirk Schlüter
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Free article

A20 expression in dendritic cells protects mice from LPS-induced mortality

Nguyen Thi Xuan et al. Eur J Immunol. 2015 Mar.
Free article

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.

Keywords: A20; Autoimmunity; DC; LPS tolerance; Mice.

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