Background/Purpose: The Bcl-2 family guards the mitochondrial apoptotic pathway. Among numerous Bcl-2 antagonists, only the loss of Bim in mice leads to the development of SLE-like disease, suggesting Bim’s unique state that exerts dominance in several pathways that are vital for the development of SLE. We have shown that reduction of Bim alters macrophage function thereby preventing the break in tolerance. We hypothesize that Bim limits inflammatory responses in macrophages and therefore prevents SLE-like disease development independent of its role in apoptosis.

Methods: We generated mice lacking Bim specifically in myeloid cells (Cre^LysMBim^fl/fl) and assessed mice at 8 months of age for characterization of SLE-like disease.  Macrophage turnover/proliferation and activation were examined in vivo using flow cytometric analyses and luminex based assays.

Results: Cre^LysMBim^fl/fl mice displayed splenomegaly, lymphadenopathy, hypergammaglobulinemia, IC deposition in the kidney, proteinuria, GN, and early mortality as compared to Bim^fl/fl and mice lacking Bim in either lymphocyte compartments. Bim functions independently of its role in apoptosis in macrophages and monocytes, because we did not detect any differences in the rate of EdU incorporation in tissue-resident macrophages and monocyte-derived populations from Bim^fl/fl and Cre^LysMBim^fl/fl mice. Cre^LysMBim^fl/fl splenic macrophages also displayed an enhanced activated phenotype that may not be due to an endogenous TLR that requires MyD88, as loss of MyD88 in Cre^LysMBim^fl/fl mice did not reverse disease phenotype. Mixed bone marrow chimera mice showed reduced disease activities, indicating that macrophages from the wild type mice are sufficient to suppress autoimmunity caused by loss of Bim in macrophages. Loss of Bim in macrophages is sufficient to induce SLE-like disease, as adoptively transferring wild type lymphocytes to Cre^LysMBim^fl/flRag^-/- mice increased glomeruli size and leukocyte infiltrates in the kidneys compared to Rag^-/- mice receiving wild type lymphocytes. The BH3 domain and JNK phosphorylation site of Bim, which are essential for apoptotic functions, are necessary for the disease development, because replacing BH3 domain or mutating the phosphorylation sites resulted in the development of SLE-like disease. Lastly, kidney macrophages can be accurately identified by multi-parameter flow cytometry, which increased in number in Cre^LysMBim^fl/fl mice. Gene expression profiling revealed that kidney macrophages from Cre^LysMBim^fl/fl exhibited M2 phenotype that is associated with collagen deposition and fibrosis in the kidney.

Conclusion: The expression of Bim in macrophages is sufficient to inhibit SLE-like pathogenesis. These data suggest that Bim acts as a molecular rheostat controlling macrophage functions through its BH3 domain and JNK phosphorylation site, which is independent of its role in apoptosis. Bim mediates macrophage inflammatory responses not only in secondary lymphoid organs (spleen), but also in end-organs (kidney). These studies are crucial for understanding the development SLE, and for translational studies leading to the development of new targets for SLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/bim-suppresses-the-development-of-sle-by-limiting-macrophage-inflammatory-responses/