Background/Purpose Only recently have monocytes and macrophages been accepted as critical players in the pathogenesis of SLE.  However, very little is known regarding the molecular rheostats that control the actions of monocytes and macrophages and their state of polarization.  Previous studies have shown that loss of Bim, a pro-apoptotic protein, in all cells leads to SLE-like disease and early mortality.  We have shown that reduction of Bim alters macrophage function independent of its role in apoptosis. Thus, we hypothesize that Bim is essential in monocytes and macrophages to limit the development of SLE-like disease. 

Methods We generated mice lacking Bim specifically in myeloid cells (Cre^LysMBim^flox/flox) and assessed mice at 8, 16, 24, 36 and 48 weeks of age for characterization of SLE-like disease.  Macrophage turnover, activation, and polarization were examined in vivo and in vitrousing flow cytometric analyses and luminex based assays. 

Results Cre^LysMBim^flox/flox mice displayed splenomegaly, lymphadenopathy, heightened amounts of serum pro-inflammatory cytokines, hypergammaglobulinemia, IC deposition in the kidney, proteinuria, GN, and early mortality as compared to Bim^flox/flox and mice lacking Bim in either lymphocyte compartments.  Bim functions independently of its role in apoptosis in macrophages and monocytes, since macrophages from Cre^LysMBim^flox/flox and from Bim^flox/flox mice had equal BrdU uptake.  Moreover, MyD88 is not necessary as Cre^LysMBim^flox/floxMyD88^flox/flox mice also developed SLE-like disease.  The protein kinase Akt was increased in macrophages from Cre^LysMBim^flox/flox mice and was co-immunoprecipatated with Bim in wild type cells.  Additionally, the BH3 domain, which is essential for its apoptotic function is necessary for suppressing inflammatory response in macrophages.  Mixed bone marrow chimeras were sufficient to reduce development of SLE-like disease in Cre^LysMBim^flox/flox mice, which suggests that Bim may affect macrophage development or polarization.  To this end, we show that Bim is necessary to prevent the skewing of macrophages towards M2, pro-fibrotic phenotype. 

Conclusion The expression of Bim in monocytes and macrophages is sufficient to inhibit SLE-like pathogenesis.  These data suggest that Bim acts through its BH3 domain to reduce the intensity of inflammation and polarization status in macrophages through suppression the activity of Akt.  These studies are crucial for understanding the development and the persistence of SLE, as well as 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-glomerulonephritis-by-inhibiting-m2-polarization/