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Bim suppresses the development of SLE by limiting myeloid inflammatory responses


Tsai, F; Homan, PJ; Agrawal, H; Misharin, AV; Abdala-Valencia, H; Haines, GK, 3rd; Dominguez, S; Bloomfield, CL; Saber, R; Chang, A; Mohan, C; Hutcheson, J; Davidson, A; Budinger, GRS; Bouillet, P; Dorfleutner, A; Stehlik, C; Winter, DR; Cuda, CM; Perlman, H
2017-11-07
J Exp Med
Journal Article in press
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-beta) 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.
Rockefeler Uni Press
Molecular Genetics of Cancer
10.1084/jem.20170479
29114065
Refer to copyright notice on published article.

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Creation Date 2017-11-29 08:57:56 Last Modified 2017-11-29 09:14:19