Abstract
We have shown that bone marrow (BM)-derived mesenchymal stem cells (BM-MSCs) from SLE patients exhibit senescent behavior and are involved in the pathogenesis of SLE. The aim of this study was to investigate the effects of rapamycin (RAPA) on the senescences and immunoregulatory ability of MSCs of MRL/lpr mice and SLE patients and the underlying mechanisms. Cell morphology, senescence associated β-galactosidase (SA-β-gal) staining, F-actin staining were used to detect the senescence of cells. BM-MSCs and purified CD4+ T cells were co-cultured indirectly. Flow cytometry was used to inspect the proportion of regulatory T (Treg) /T helper type 17 (Th17). We used small interfering RNA (siRNA) to interfere the expression of mTOR, and detect the effects by RT-PCR, WB and immunofluorescence. Finally, 1×106 of SLE BM-MSCs treated with RAPA were transplanted to cure the 8 MRL/lpr mice aged 16 weeks for 12 weeks. We demonstrated that RAPA alleviated the clinical symptoms of lupus nephritis and prolonged survival in MRL/lpr mice. RAPA reversed the senescent phenotype and improved immunoregulation of MSCs from MRL/lpr mice and SLE patients through inhibition of the mTOR signaling pathway. Marked therapeutic effects were observed in MRL/lpr mice following transplantation of BM-MSCs from SLE patients pretreated with RAPA.
Highlights
Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease characterized by multi-organ involvement and a remarkable variability in clinical presentation [1]
Carrion and coworkers reported that autologous bone marrow (BM)-Mesenchymal stem cells (MSCs) transplantation (MSCT) had no effect on disease activity in two SLE patients [25]. These findings suggested that the senescence of MSCs from SLE patients may contribute to the disease pathogenesis
Since 1994, when the significant reduction or prevention of the many pathologic features of lupus normally seen in the MRL/l mouse mediated by RAPA were first reported [44], there have been an increasing number of studies focusing on RAPA treatment of lupus
Summary
Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease characterized by multi-organ involvement and a remarkable variability in clinical presentation [1]. It is a typical autoimmune disease based on the variety of its proposed pathogenesis, including abnormalities of T and B. With recent advances in our understanding of the underlying pathology, several new strategies have been developed to target specific activation pathways relevant to the pathogenesis of SLE [4, 5]. B-celldepleting therapies using the monoclonal antibody rituximab and the B lymphocyte stimulator (BLyS) inhibitor belimumab, have been shown be beneficial in a specific subpopulation of lupus patients [6, 7]
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