Bim suppresses the development of SLE by limiting myeloid inflammatory responses

Abstract

Tsai et al. demonstrate that loss of Bim (BCL2L11) in myeloid cells in mice (LysM ^CreBim ^fl/fl) is sufficient to induce systemic autoimmunity. Kidney macrophages in LysM ^CreBim ^fl/fl mice possess a proinflammatory transcriptional signature and signal through TRIF to cause end-stage glomerulonephritis.

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 (LysM ^CreBim ^fl/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. LysM ^CreBim ^fl/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 LysM ^CreBim ^fl/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.