Session Type: ACR Concurrent Abstract Session
Session Time: 4:30PM-6:00PM
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 status that exerts dominance in several pathways that are vital for the development of SLE. However, the role that Bim plays in macrophage functions and relevance to SLE is unknown.
Methods: We generated mice lacking Bim specifically in macrophages (CreLysMBimfl/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. To better understand the role of Bim in regulating transcriptional profile in kidney macrophages, RNA-seq analysis was performed on sorted macrophages from CreLysMBimfl/fl and Bimfl/fl mice.
Results: CreLysMBimfl/fl mice displayed splenomegaly, lymphadenopathy, hyperglobulinemia, IC deposition in the kidney, proteinuria, GN, and early mortality as compared to Bimfl/fl and mice lacking Bim in either lymphocyte compartments. CreLysMBimfl/fl mice were lack of splenic marginal zone macrophages (MZMs) and marginal zone B cells (MZ-B cells), which is also evident in lupus patients. Bim functions in macrophages are independent of its role in apoptosis as there were no differences in the rate of EdU incorporation in macrophages from Bimfl/fl and CreLysMBimfl/fl mice. TLRs, the well-known initiators of autoimmune disease, are not required for the break in tolerance, as mice lacking MyD88 or TRIF in CreLysMBimfl/fl mice (MyD88fl/fl CreLysMBimfl/fl and TRIF -/- CreLysMBimfl/fl) developed systemic autoimmunity similar to CreLysMBimfl/fl mice. However, TRIF-/-CreLysMBimfl/fl mice did not develop end-stage GN. Consistent with these data, CreLysMBimfl/fl mice showed increased numbers of kidney macrophages, while TRIF -/- CreLysMBimfl/fl mice exhibited significantly reduced numbers as identified by multi-parameter flow cytometry. To better understand the effect of Bim deletion in kidney macrophages in vivo, we utilized RNA-seq for FACSorted kidney macrophages from young and old mice. Exploratory analysis via principal component analysis (PCA) revealed that Bim deletion affected the transcriptional profile of kidney macrophages. We were able to identify unique cellular processes up-regulated in CreLysMBimfl/fl kidney macrophages using pairwise GO processes analyses. We also identified that kidney macrophages from CreLysMBimfl/fl mice significantly up-regulate ifnar1, the receptor for IFNα and IFNβ.
Conclusion: The expression of Bim in macrophages is sufficient to inhibit SLE-like pathogenesis. Bim controls macrophage functions independent of its role in apoptosis which challenges the conventional dogma that Bim’s role in autoimmunity is to prevent the escape of autoreactive lymphocytes from apoptosis. We provide data to identify the role of kidney macrophages throughout SLE-like disease development in the context of Bim deficiency. The discovery of Bim-regulated transcriptome in kidney macrophages are crucial for translational studies leading to the development of new targets for SLE.
To cite this abstract in AMA style:Tsai F, Cuda C, Perlman HR, Homan PJ, Dominguez S, Shaffer A, Haines GK III, Hutcheson J. Bim Suppresses the Development of SLE By Limiting Macrophage Inflammatory Responses [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/bim-suppresses-the-development-of-sle-by-limiting-macrophage-inflammatory-responses-2/. Accessed July 6, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/bim-suppresses-the-development-of-sle-by-limiting-macrophage-inflammatory-responses-2/