Bim Regulates Myeloid Cell Homeostasis to Control Systemic AutoimmunityPublic Deposited
The Bcl-2 family is considered the guardian of the mitochondrial apoptotic pathway. While there are numerous endogenous Bcl-2 antagonists that share similar homology, structure, topology, and expression pattern, only the loss of Bim in mice is sufficient to lead to the development of a systemic autoimmunity. Even loss of both quintessential pro-apoptotic Bcl-2 family executioners, Bak and Bax does not break tolerance. Thus, Bim’s unique status suggest that it exerts dominance in several pathways that are vital for development of systemic autoimmunity, independent of its role in inducing the apoptotic cascade. Since monocytes and macrophages play crucial roles in the pathogenesis of SLE, this thesis will focus on Bim’s function in controlling the actions of monocytes and macrophages. In this work, we demonstrated that Bim plays an anti-inflammatory role in monocytes and macrophages to suppress the development of SLE-like disease. As mice lacking Bim in myeloid cells including macrophages (LysMCreBimfl/fl) develop SLE-like disease that mirrors aged Bim-/- mice. LysMCreBimfl/fl mice develop splenomegaly, lymphadenopathy, autoantibodies including anti-DNA IgG and a type I IFN response as compared to control mice, CD4CreBimfl/fl, dLckCreBimfl/fl and CD19CreBimfl/fl mice. Further, while splenic macrophages are hyperactivated in LysMCreBimfl/fl mice, there is a decrease in splenic marginal zone macrophages from LysMCreBimfl/fl mice, which might lead to increased numbers of apoptotic bodies that could contribute to the development of systemic autoimmunity. The loss of Bim in macrophages is sufficient to break tolerance as adoptive transfer of wild-type lymphocytes into Rag-/-LysMCreBimfl/fl mice leads to systemic autoimmunity. LysMCreBimfl/fl mice also exhibited increased mortality attributed to immune complex deposition and increased numbers of kidney macrophages. Moreover, we identified TRIF is required for progression of end-stage glomerulonephritis, but is dispensable for systemic autoimmunity. RNA-seq analysis revealed that Bim-deleted kidney macrophages exhibited a pro-inflammatory transcriptional signature that was detectable in other murine model of SLE-like disease and lupus nephritis patients.