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

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(Cre)Bim(fl/fl)) develop a systemic lupus erythematosus (SLE)-like disease that mirrors aged Bim-/-mice, including loss of marginal zone macrophages, splenomegaly, lymphadenopathy, auto-antibodies (including anti-DNA IgG), and a type I interferon signature. LysM(Cre)Bim(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-beta) is essential for GN, but not systemic autoimmunity in LysM(Cre)Bim(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.