SH3BP2 Deficiency Ameliorates Murine Systemic Lupus Erythematosus.

Kyoko Kawahara,Hajime Nagasu,Tomoyuki Mukai,Sumie Hiramatsu-Asano,Yoshitaka Morita,Yasuyoshi Ueki,Naoki Kashihara,Katsuhiko Ishihara,Akiko Nagasu,Shoko Tsuji,Masanori Iseki,Takahiko Akagi

doi:10.3390/ijms22084169

Abstract

Background: The adaptor protein Src homology 3 domain-binding protein 2 (SH3BP2) is widely expressed in immune cells. It controls intracellular signaling pathways. The present study was undertaken to investigate the role of SH3BP2 in a murine systemic lupus erythematosus model. Methods: For the lupus model, we used Faslpr/lpr mice. Clinical and immunological phenotypes were compared between Faslpr/lpr and SH3BP2-deficient Faslpr/lpr mice. Splenomegaly and renal involvement were assessed. Lymphocyte subsets in the spleen were analyzed by flow cytometry. To examine the role of SH3BP2 in specific cells, B cell-specific SH3BP2-deficient lupus mice were analyzed; T cells and bone marrow-derived dendritic cells and macrophages were analyzed in vitro. Results: SH3BP2 deficiency significantly reduced lupus-like phenotypes, presented as splenomegaly, renal involvement, elevated serum anti-dsDNA antibody, and increased splenic B220+CD4−CD8− T cells. Notably, SH3BP2 deficiency in B cells did not rescue the lupus-like phenotypes. Furthermore, SH3BP2 deficiency did not substantially affect the characteristics of T cells and macrophages in vitro. Interestingly, SH3BP2 deficiency suppressed the differentiation of dendritic cells in vitro and reduced the number of dendritic cells in the spleen of the lupus-prone mice. Conclusions: SH3BP2 deficiency ameliorated lupus-like manifestations. Modulating SH3BP2 expression could thus provide a novel therapeutic approach to autoimmune diseases.

Highlights

Quantitative PCR and immunoblot analyses revealed that Src homology 3 domain-binding protein 2 (SH3BP2) mRNA and protein are expressed in T cells, B cells, macrophages, and dendritic cells
The expression levels are relatively higher in B cells, macrophages, and dendritic cells compared to T cells (Figure A1a,b, Appendix A)
We first confirmed that SH3BP2 protein was deleted in the tissues of the SH3BP2-deficient mice (Figure 1a); SH3BP2 protein levels in the tissues were not altered by the Faslpr/lpr mutation (Figure 1a)

Summary

Introduction

Systemic lupus erythematosus (SLE) is an autoimmune disease influenced by genetic and environmental factors and is characterized by dysregulated immune responses such as loss of self-tolerance to cellular antigens and autoantibody production [1]. Autoantibody production causes immune complex formation, resulting in local and systemic inflammation and organ damage [1]. The lupus-prone mice develop massive lymphoproliferation and multiple-organ damage associated with increased autoreactive lymphocytes and autoantibodies, such as the anti-double-stranded DNA (dsDNA). The adaptor protein Src homology 3 domain-binding protein 2 (SH3BP2) is widely expressed in immune cells. The present study was undertaken to investigate the role of SH3BP2 in a murine systemic lupus erythematosus model

Methods

Results

Conclusion