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Bcl-3 inhibits lupus-like phenotypes in BL6/lpr mice.

Authors :
Tang W
Wang H
Tian R
Saret S
Cheon H
Claudio E
Siebenlist U
Source :
European journal of immunology [Eur J Immunol] 2021 Jan; Vol. 51 (1), pp. 197-205. Date of Electronic Publication: 2020 Jul 29.
Publication Year :
2021

Abstract

Bcl-3 is an atypical member of the IκB family that modulates NF-κB activity in nuclei. lpr mice carry the lpr mutation in Fas, resulting in functional loss of this death receptor; they serve as models for lupus erythematosus and autoimmune lymphoproliferation syndrome (ALPS). To explore the biologic roles of Bcl-3 in this disease model, we generated BL6/lpr mice lacking Bcl-3. Unlike lpr mice on an MRL background, BL6/lpr mice present with very mild lupus- or ALPS-like phenotypes. Bcl-3 KO BL6/lpr mice, however, developed severe splenomegaly, dramatically increased numbers of double negative T cells - a hallmark of human lupus, ALPS, and MRL/lpr mice - and exhibited inflammation in multiple organs, despite low levels of autoantibodies, similar to those in BL6/lpr mice. Loss of Bcl-3 specifically in T cells exacerbated select lupus-like phenotypes, specifically organ infiltration. Mechanistically, elevated levels of Tnfα in Bcl-3 KO BL6/lpr mice may promote lupus-like phenotypes, since loss of Tnfα in these mice reversed the pathology due to loss of Bcl-3. Contrary to the inhibitory functions of Bcl-3 revealed here, this regulator has also been shown to promote inflammation in different settings. Our findings highlight the profound, yet highly context-dependent roles of Bcl-3 in the development of inflammation-associated pathology.<br /> (Published 2020. This article is a U.S. Government work and is in the public domain in the USA.)

Details

Language :
English
ISSN :
1521-4141
Volume :
51
Issue :
1
Database :
MEDLINE
Journal :
European journal of immunology
Publication Type :
Academic Journal
Accession number :
32652549
Full Text :
https://doi.org/10.1002/eji.202048584