Presenting Author:
Principal Investigator:
Department:
Medicine
Keywords:
apoptosis, systemic lupus erythematosus, kidney macrophages, glomerulonephritis, TLR signaling adaptor protein, RNA-seq,... [Read full text]
Location:
Third Floor, Feinberg Pavilion, Northwestern Memorial Hospital
B34 - Basic Science Women's Health Research
Bim Regulates Transcriptional Profile of Macrophages to Suppress SLE-like Disease
Recent studies have shown that kidney macrophage infiltrates correspond to poor prognosis in human systemic lupus erythematosus (SLE). Renal macrophages from SLE patients are increased in number and exhibit elevated expression of activation markers. Studies in murine models also support the importance of monocytes and macrophages in the pathogenesis of SLE-like disease. However, very little is known about the global changes in macrophage function as a result of disease. The apoptotic proteins of the Bcl-2 protein family consist of two types: those with multiple Bcl-2 homology domains, including Bak, Bax, Bok and Bcl-x5 and those which contain only a single BH3 domain, including Bim, Bad, Bid, Noxa and Puma. Only mice deficient in Bim develop spontaneous SLE-like disease. Given the role of Bim as a mediator of cell death and the lymphocyte-centric hypothesis of SLE development, significant attention has understandably been paid to the role that Bim plays in eliminating self-reactive lymphocytes. However, Bim deficiency also impacts innate immune cell populations. Little is known about the role of Bim in innate immune cells and how it contributes to systemic autoimmunity. In this study, we demonstrate that macrophages are central initiators of SLE-like disease, as mice lacking Bim specifically in macrophages (LysMCreBimfl/fl) display hallmarks of SLE-like diseases including splenomegaly, autoantibodies and a type I IFN signature. LysMCreBimfl/fl mice also exhibit increased mortality attributed to glomerulonephritis (GN) due to increased kidney macrophage infiltrations. RNA-seq analysis on sorted kidney macrophages reveals that loss of Bim leads kidney macrophages acquire a pro-inflammatory transcriptional profile. Our results suggest that TLR signaling adaptor protein, TRIF, is essential for progression to GN phase but is dispensable for systemic autoimmunity. Deletion of TRIF in LysMCreBimfl/fl mice (TRIF-/-LysMCreBimfl/fl) rescued GN and reduced kidney macrophage infiltration. We analyze the effect of TRIF on the transcriptional profile of LysMCreBimfl/fl kidney macrophages using RNA-seq. K-means clustering (K=4) of the 5,694 differentially expressed genes compared between control and LysMCreBimfl/fl kidney macrophages and between TRIF-/-LysMCreBimfl/fl and LysMCreBimfl/fl kidney macrophages reveals a key cluster that is regulated by both Bim and TRIF—our Lupus Nephritis (LN) signature. GO analysis reveals that the genes in this LN signature are enriched for immune responses. Notably, LysMCreBimfl/fl kidney macrophages share transcriptional profiles with human LN, including IFN-inducible genes, such as LY6E and ISG15. In conclusion, we establish a novel model of SLE-like disease that is mediated by macrophages in the context of Bim. Further, our data demonstrate that Bim may be useful for the novel therapeutic strategies that target macrophages for the treatment of SLE.
