Abstract
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease involving multiple organs and systems. Mesenchymal stem cells (MSCs) from SLE patients have demonstrated defects such as impaired growth, senescence phenotype and immunomodulatory functions. Some studies have suggested the close connection between inflammation microenvironment and cellular senescence. In the current study, we detected cytokines levels in bone marrow supernatant by the quantitative proteomics analysis, and found the expression of HMGB1 was remarkably increased in bone marrow from SLE patients. Senescence associated-β-galactosidase (SA-β-gal) staining, F-actin staining and flow cytometry were used to detect the senescence of cells. After stimulation of HMGB1 in normal MSCs, the ratio of SA-β-gal positive in BM-MSCs was increased, the organization of cytoskeleton was disordered, and TLR4-NF-κB signaling was activated. Finally, Ethyl pyruvate (EP) (40 mg/kg and 100 mg/kg, three times a week), a high security HMGB1 inhibitor, was injected intraperitoneally to treat MRL/lpr mice for 8 weeks. We demonstrated that EP alleviated the clinical aspects of lupus nephritis and prolonged survival of MRL/lpr mice. In the meantime, EP reversed the senescent phenotype of BM-MSCs from MRL/lpr mice. HMGB1 could be a promising target in SLE patients, and might be one of the reasons of recurrence after MSCs transplantation.
Highlights
Systemic lupus erythematosus (SLE), a chronic autoimmune disease, involves multiple organs and systems and influences patients on health and life severely [1]
To verify the data from proteomics results, bone marrow supernatant level of HMGB1 was measured by ELISA, and the elevated expression of HMGB1 was detected in SLE patients, compared to the healthy control (Figure 1B)
Our results showed there were more SA-βgal-positive cells in BM-Mesenchymal stem cells (MSCs) when treated with bone marrow supernatant from SLE patients, interestingly, which could be reversed by a neutralizing anti-HMGB1 monoclonal antibody (Figure 2A, 2B)
Summary
Systemic lupus erythematosus (SLE), a chronic autoimmune disease, involves multiple organs and systems and influences patients on health and life severely [1]. Previous study showed that allogenic MSC transplantation (MSCT) seemed to be a safe and effective therapeutic strategy in refractory SLE [4]. Our and other group reported that BMMSCs from SLE patients showed characteristics of senescence, appearing increased Senescence associated- β-galactosidase (SA-β-gal) activity, cell cycle arrest, disordered F-actin distribution and reduced ability of regulating Treg [6]. Reversing senescence of SLE MSCs pretreated with rapamycin in vitro could alleviate the clinical symptoms of lupus nephritis and prolong survival in MRL/lpr mice [7]. These studies revealed that senescent BM-MSCs might be associated with the pathogenesis of SLE. It reminded us to discover the senescence mechanism of BM-MSCs thoroughly
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