Year: 2017
Type: article
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.
DOI: 10.1084/jem.20170479
Authors: FuNien Tsai, Philip J. Homan, Hemant Agrawal, Alexander V. Misharin, Hiam Abdala-Valencia, G. Kenneth Haines, Salina Dominguez, Christina L. Bloomfield, Rana Saber, Anthony Chang, Chandra Mohan, Jack Hutcheson, Anne Davidson, G.R. Scott Budinger, Philippe Bouillet, Andrea Dorfleutner, Christian Stehlik, Deborah R. Winter, Carla M. Cuda, Harris Perlman
Language: English
Subfield: Rheumatology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Funders: American Heart Association, United States - Israel Binational Science Foundation, Rheumatology Research Foundation, Northwestern University, Cincinnati Children's Hospital Medical Center, University of Cincinnati, United States-Israel Binational Science Foundation, National Institutes of Health, College of Medicine, University of Cincinnati, National Institute on Aging, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of Allergy and Infectious Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Center for Advancing Translational Sciences
Awards: G1127494963, G1187687215, G1284175734, G1382277591, G1444394703, G1520748404, Cardiovascular Regenerative Medicine, Postdoctoral Rheumatology Training, G317886719, Development of a Novel RA/Atherosclerosis Mouse Model, G474454551, Northwestern University Clinical and Translational Science Institute (NUCATS), G5047955515, FACSAria SORP Cell Sorter, G659096663, G687483644, G6884127972, G6919352606, G7356645039, G7473363761, G8220594877, Inflammasome adaptor and effectors in Cryopyrinopathies and crystal arthropathies, G8907595608, G9000046704, G9000077581, G9000127942, G9000134880, G9000222627, G9000242227, The Robert H. Lurie Comprehensive Cancer Center
OpenAlex ID: W2767541865