Wang, Xu, Nishanth, Gopala, Waisman, Ari ORCID: 0000-0003-4304-8234, Borucki, Katrin, Isermann, Berend, Naumann, Michael
ORCID: 0000-0002-8060-2313, Deckert, Martina and Schlueter, Dirk
(2015).
A20 expression in dendritic cells protects mice from LPS-induced mortality.
Eur. J. Immunol., 45 (3).
S. 818 - 829.
HOBOKEN:
WILEY.
ISSN 1521-4141
Abstract
DCs contribute to immune homeostasis under physiological conditions and regulate the immune activation during infection. The deubiquitinase A20 inhibits the activation of NF-B-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-, and TNF. Upon LPS stimulation, the activation of NF-B 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.
Item Type: | Journal Article | ||||||||||||||||||||||||||||||||||||
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URN: | urn:nbn:de:hbz:38-406799 | ||||||||||||||||||||||||||||||||||||
DOI: | 10.1002/eji.201444795 | ||||||||||||||||||||||||||||||||||||
Journal or Publication Title: | Eur. J. Immunol. | ||||||||||||||||||||||||||||||||||||
Volume: | 45 | ||||||||||||||||||||||||||||||||||||
Number: | 3 | ||||||||||||||||||||||||||||||||||||
Page Range: | S. 818 - 829 | ||||||||||||||||||||||||||||||||||||
Date: | 2015 | ||||||||||||||||||||||||||||||||||||
Publisher: | WILEY | ||||||||||||||||||||||||||||||||||||
Place of Publication: | HOBOKEN | ||||||||||||||||||||||||||||||||||||
ISSN: | 1521-4141 | ||||||||||||||||||||||||||||||||||||
Language: | English | ||||||||||||||||||||||||||||||||||||
Faculty: | Unspecified | ||||||||||||||||||||||||||||||||||||
Divisions: | Unspecified | ||||||||||||||||||||||||||||||||||||
Subjects: | no entry | ||||||||||||||||||||||||||||||||||||
Uncontrolled Keywords: |
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URI: | http://kups.ub.uni-koeln.de/id/eprint/40679 |
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