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J Exp Med. 2017 Dec 4;214(12):3753-3773. doi: 10.1084/jem.20170479. Epub 2017 Nov 7.

Bim suppresses the development of SLE by limiting myeloid inflammatory responses.

Author information

1
Division of Rheumatology, Feinberg School of Medicine, Northwestern University, Chicago, IL.
2
TTP Labtech India Private Limited, Faridabad, India.
3
Division of Pulmonary and Critical Care, Feinberg School of Medicine, Northwestern University, Chicago, IL.
4
Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY.
5
Department of Pathology, University of Chicago, Chicago, IL.
6
Department of Biomedical Engineering, University of Houston, Houston, TX.
7
Tri-Service Research Laboratory, San Antonio, TX.
8
The Feinstein Institute for Medical Research, Hofstra Northwell School of Medicine, Manhasset, NY.
9
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
10
Division of Rheumatology, Feinberg School of Medicine, Northwestern University, Chicago, IL c-cuda@northwestern.edu.
11
Division of Rheumatology, Feinberg School of Medicine, Northwestern University, Chicago, IL h-perlman@northwestern.edu.

Abstract

The Bcl-2 family is considered the guardian of the mitochondrial apoptotic pathway. We demonstrate that Bim acts as a molecular rheostat by controlling macrophage function not only in lymphoid organs but also in end organs, thereby preventing the break in tolerance. Mice lacking Bim in myeloid cells (LysMCreBimfl/fl) develop a systemic lupus erythematosus (SLE)-like disease that mirrors aged Bim-/- mice, including loss of marginal zone macrophages, splenomegaly, lymphadenopathy, autoantibodies (including anti-DNA IgG), and a type I interferon signature. LysMCreBimfl/fl mice exhibit increased mortality attributed to glomerulonephritis (GN). Moreover, the toll-like receptor signaling adaptor protein TRIF (TIR-domain-containing adapter-inducing interferon-β) is essential for GN, but not systemic autoimmunity in LysMCreBimfl/fl mice. Bim-deleted kidney macrophages exhibit a novel transcriptional lupus signature that is conserved within the gene expression profiles from whole kidney biopsies of patients with SLE. Collectively, these data suggest that the Bim may be a novel therapeutic target in the treatment of SLE.

PMID:
29114065
PMCID:
PMC5716039
DOI:
10.1084/jem.20170479
[Indexed for MEDLINE]
Free PMC Article

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