BCL-2 antagonists kill plasmacytoid dendritic cells of lupus-prone mice and dampen IFN-alpha production

Zhan, Y; Carrington, EM; Ko, HJ; Vikstrom, IB; Oon, S; Zhang, JG; Vremec, D; Brady, JL; Bouillet, P; Wu, L; Huang, DC; Wicks, IP; MORAND, EF; Strasser, A; Lew, AM

Author(s): Zhan, Y; Carrington, EM; Ko, HJ; Vikstrom, IB; Oon, S; Zhang, JG; Vremec, D; Brady, JL; Bouillet, P; Wu, L; Huang, DC; Wicks, IP; MORAND, EF; Strasser, A; Lew, AM;
Details: Publication Year 2014-11-21,Volume 67,Issue #3,Page 797-808
Journal Title: Arthritis Rheumatol
Publication Type: Journal Article
Abstract: Objective: IFN-alpha producing plasmacytoid DCs (pDCs) are implicated in the pathogenesis of systemic lupus erythematosus (SLE). IFN-alpha related genes are highlighted among SLE susceptibility alleles and they are characteristically expressed in SLE blood, while in mouse lupus models, pDC numbers and IFN-alpha production are increased. Here we interrogate the effects on pDC survival of inhibitors that selectively target different anti-apoptotic molecules. Methods: pDC numbers, in vitro survival and expression of anti-apoptotic molecules were evaluated in lupus-prone NZB/W F1 mice. The impact of BCL-2 antagonists and glucocorticoids on pDCs were evaluated in vitro and in vivo. IFN-alpha production by NZB/W F1 mice was evaluated before and after treatment with BCL-2 antagonists. Results: pDCs but not lymph-resident conventional DCs (cDCs) largely rely on the anti-apoptotic protein BCL-2 for survival. The enlarged pDC compartment in NZB/W F1 mice is associated with selectively prolonged survival and increased BCL-2 transcription. Functionally, this results in enhanced production of IFN-alpha. BCL-2 inhibitors selectively kill mouse and human pDCs, including pDCs from SLE patients, but not cDCs, dampens IFN-alpha production by pDCs and synergizes with glucocorticoids to kill activated pDCs. Conclusion: Enhanced pDC survival is a likely contributing factor for enhanced IFN-alpha production by lupus pDCs. BCL-2 antagonists potently and selectively kill pDCs and reduce IFN-alpha production; thus, we contend that they are attractive candidates for treating pDC-associated diseases. This article is protected by copyright. All rights reserved.
Publisher: Wiley
Research Division(s): Immunology; Molecular Genetics Of Cancer; Cancer And Haematology; Inflammation
Publisher's Version: https://doi.org/10.1002/art.38966
NHMRC Grants: NHMRC/1037321, NHMRC/1016647, NHMRC/637324, NHMRC/1007703, NHMRC/1043414, NHMRC/1021374, NHMRC/1043149, NHMRC/1020363,
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2014-11-26 08:29:04

Last Modified: 2016-03-16 10:29:29