TY - JOUR
T1 - Bim suppresses the development of SLE by limiting myeloid inflammatory responses
AU - Tsai, Fu Nien
AU - Homan, Philip J.
AU - Agrawal, Hemant
AU - Misharin, Alexander V.
AU - Abdala-Valencia, Hiam
AU - Haines, G. Kenneth
AU - Dominguez, Salina
AU - Bloomfield, Christina L.
AU - Saber, Rana
AU - Chang, Anthony
AU - Mohan, Chandra
AU - Hutcheson, Jack
AU - Davidson, Anne
AU - Scott Budinger, G. R.
AU - Bouillet, Philippe
AU - Dorfleutner, Andrea
AU - Stehlik, Christian
AU - Winter, Deborah R.
AU - Cuda, Carla M.
AU - Perlman, Harris
N1 - Funding Information:
The research was supported by the American Heart Association (grant PRE21410010 to F. Tsai), the National Institutes of Health (grant K01AR064313 to C.M. Cuda and grants HL108795, AR050250, AR054796, AR064546, and AI092490 to H. Perlman), the United States-Israel Binational Science Foundation (grant 2013247), the Rheumatology Research Foundation (grant Agmt 05/06/14), and the Mabel Green Myers Chair of Medicine (H. Perlman). Flow Cytometry Cell Sorting was performed on a BD FACSAria SORP system, which was purchased through the support of the National Institutes of Health (grant 1S10OD011996-01). Flow cytometry and histology services were provided by the Northwestern University Lurie Cancer Flow Cytometry facility and Mouse Histology and Phenotyping Laboratory, which are supported by the National Cancer Institute (grant P30-CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center). The authors declare no competing financial interests.
Publisher Copyright:
© 2017 Tsai et al.
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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.
AB - 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.
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U2 - 10.1084/jem.20170479
DO - 10.1084/jem.20170479
M3 - Article
C2 - 29114065
AN - SCOPUS:85036552613
SN - 0022-1007
VL - 214
SP - 3753
EP - 3773
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 12
ER -