Overexpression of Mcl-1 exacerbates lymphocyte accumulation and autoimmune kidney disease in lpr mice

Anstee, N. S., Vandenberg, C. J., Campbell, K. J., Hughes, P. D., O’Reilly, L. A. and Cory, S. (2017) Overexpression of Mcl-1 exacerbates lymphocyte accumulation and autoimmune kidney disease in lpr mice. Cell Death and Differentiation, 24(3), pp. 397-408. (doi: 10.1038/cdd.2016.125) (PMID:27813531) (PMCID:PMC5344201)

Abstract

Cell death by apoptosis has a critical role during embryonic development and in maintaining tissue homeostasis. In mammals, there are two converging apoptosis pathways: the ‘extrinsic’ pathway, which is triggered by engagement of cell surface ‘death receptors’ such as Fas/APO-1; and the ‘intrinsic’ pathway, which is triggered by diverse cellular stresses, and is regulated by prosurvival and pro-apoptotic members of the Bcl-2 family of proteins. Pro-survival Mcl-1, which can block activation of the proapoptotic proteins, Bax and Bak, appears critical for the survival and maintenance of multiple haemopoietic cell types. To investigate the impact on haemopoiesis of simultaneously inhibiting both apoptosis pathways, we introduced the vavP-Mcl-1 transgene, which causes overexpression of Mcl-1 protein in all haemopoietic lineages, into Faslpr/lpr mice, which lack functional Fas and are prone to autoimmunity. The combined mutations had a modest impact on myelopoiesis, primarily an increase in the macrophage/monocyte population in Mcl-1tg/lpr mice compared with lpr or Mcl-1tg mice. The impact on lymphopoiesis was striking, with a marked elevation in all major lymphoid subsets, including the non-conventional double-negative (DN) T cells (TCRβ+ CD4– CD8– B220+ ) characteristic of Faslpr/lpr mice. Of note, the onset of autoimmunity was markedly accelerated in Mcl-1tg/lpr mice compared with lpr mice, and this was preceded by an increase in immunoglobulin (Ig)-producing cells and circulating autoantibodies. This degree of impact was surprising, given the relatively mild phenotype conferred by the vavP-Mcl-1 transgene by itself: a two- to threefold elevation of peripheral B and T cells, no significant increase in the non-conventional DN T-cell population and no autoimmune disease. Comparison of the phenotype with that of other susceptible mice suggests that the development of autoimmune disease in Mcl-1tg/lpr mice may be influenced not only by Ig-producing cells but also other haemopoietic cell types.

• Item Type: Articles
• Additional Information: This project was supported by NHMRC (Australia) program grants 461221, 1016701 and 1016647, National Cancer Institute grant CA43540, Leukemia and Lymphoma Society Specialized Center for Research grants 7015-02 and 7001-13, PhD fellowship from the Leukemia Foundation of Australia (NSA); postdoctoral fellowships from EMBO and the Human Frontier in Science Program (KJC); and infrastructure support to Walter and Eliza Hall Institute from the National Health and Medical Research (NHMRC) Independent Research Institute Infrastructure Support Scheme and the Victorian State Government Operational Infrastructure Support.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Campbell, Dr Kirsteen
• Authors: Anstee, N. S., Vandenberg, C. J., Campbell, K. J., Hughes, P. D., O’Reilly, L. A., and Cory, S.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Cell Death and Differentiation
• Publisher: Nature Publishing Group
• ISSN: 1350-9047
• ISSN (Online): 1476-5403
• Published Online: 04 November 2016
• Copyright Holders: Copyright © 2017 The Authors
• First Published: First published in Cell Death and Differentiation 24(3): 397-408
• Publisher Policy: Reproduced under a Creative Commons license