Targeting HMGB1 by ethyl pyruvate ameliorates systemic lupus erythematosus and reverses the senescent phenotype of bone marrow-mesenchymal stem cells

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.

Increased serum calpain activity is associated with HMGB1 levels in systemic sclerosis

“…Consistent with previous findings, our results also showed that serum calpain activity was correlated with serum HMGB1 levels and plateletrelated parameters (MPV, PCT, and P-LCR), which suggest that activated platelet-derived calpain and HMGB1 may be responsible for the vascular remodeling and endothelial damage in patients with SSc. HMGB1 has been widely reported as a central role in the pathogenesis of many CTD, such as SLE, polymyositis or dermatomyositis with ILD, and RA [37][38][39][40][41]. Our results clearly demonstrate that serum HMGB1 levels from SSc patients are significantly higher compared with those from HC.…”

Increased serum calpain activity is associated with HMGB1 levels in systemic sclerosis

“…Moreover, several studies have demonstrated that microparticles are higher in the blood of patients with SSc compared with HC and that most of them are derived from platelets, indicating that platelet could be a critical factor in the activation of innate immunity[35,36]. Manfredi and colleagues have revealed that platelet-derived microparticles express DAMP HMGB1 and lead to initiate fibrosis and endothelial damage when injected into mice, indicating derived calpain and HMGB1 may be responsible for the vascular remodeling and endothelial damage in patients with SSc.HMGB1 has been widely reported as a central role in the pathogenesis of many CTD, such as SLE, polymyositis or dermatomyositis with ILD, and RA[37][38][39][40][41]. Our results clearly demonstrate that serum HMGB1 levels from SSc patients are significantly higher compared with those from HC.…”

Increased serum calpain activity is associated with HMGB1 levels in systemic sclerosis

“…Manfredi and colleagues have revealed that platelets-derived microparticles express DAMP HMGB1 and lead to initiate fibrosis and endothelial damage when injected into mice, indicating that platelets-associated HMGB1 may be a potential indicator of SSc[25]. Consistent with previous findings, our results also showed that serum calpain activity was correlated with serum HMGB1 levels and platelet-related parameters (MPV, PCT and P-LCR), which suggest that activated platelet-derived calpain and HMGB1 may be responsible for the vascular remodeling and endothelial damage in patients with SSc.HMGB1 has been widely reported as a central role in the pathogenesis of many CTD, such as SLE, polymyositis or dermatomyositis with ILD, and RA[39][40][41][42][43]. Our results clearly demonstrate that serum HMGB1 levels from SSc patients are significantly higher compared with that from HC.…”