TNF-αInduced the Enhanced Apoptosis of Mesenchymal Stem Cells in Ankylosing Spondylitis by Overexpressing TRAIL-R2

Abstract

Ankylosing spondylitis (AS) is an autoimmune disease with unknown etiology. Dysregulated mesenchymal stem cells (MSCs) apoptosis may contribute to the pathogenesis of autoimmune diseases. However, apoptosis of MSCs from patients with AS (ASMSCs) has not been investigated yet. The present study aims to assess the apoptosis of bone marrow-derived ASMSCs and to investigate the underlying mechanisms of altered ASMSCs apoptosis. We successfully induced the apoptosis of ASMSCs and MSCs from healthy donors (HDMSCs) using the combination of tumor necrosis factor alpha (TNF-α) and cycloheximide (CHX). We found that ASMSCs treated with TNF-α and CHX showed higher apoptosis levels compared to HDMSCs. During apoptosis, ASMSCs expressed significantly more TRAIL-R2, which activated both the death receptor pathway and mitochondria pathway by increasing the expression of FADD, cleaved caspase-8, cytosolic cytochrome C, and cleaved caspase-3. Inhibiting TRAIL-R2 expression using shRNA eliminated the apoptosis differences between HDMSCs and ASMSCs by partially reducing ASMSCs apoptosis but minimally affecting that of HDMSCs. Furthermore, the expression of FADD, cleaved caspase-8, cytosolic cytochrome C, and cleaved caspase-3 were comparable between HDMSCs and ASMSCs after TRAIL-R2 inhibition. These results indicated that increased TRAIL-R2 expression results in enhanced ASMSCs apoptosis and may contribute to AS pathogenesis.

The Phenotype and Secretory Activity of Adipose-Derived Mesenchymal Stem Cells (ASCs) of Patients with Rheumatic Diseases

“…Thus, presence of HLA-DR molecules on some HD/ASC and RD/ASC lines, observed in our study ( Figure 1D), is unsurprising. Altogether, our results show that in terms of surface marker expression, RD/ASCs resemble ASCs obtained from healthy volunteers, which is consistent with other reports [36][37][38].…”

The Role of TNF-α induced MSCs on Suppressive Inflammation by Increasing TGF-β and IL-10

“…A higher dose of TNF-α cause downregulation of MSCs type-2 signalling and induce apoptotic program through TNF-related apoptosis-inducing ligand-receptor 2 (TRAIL-R2) pathway. The similar study has reported that TNF-α may induce apoptotic through TRAIL-R2 pathway [ 24 ]. TRAIL-R2 is a specific cell surface receptor belongs to the TNF receptor superfamily [ 25 ] that also expressed in MSCs [ 26 ] [ 27 ].…”

Critical Role of Tumor Necrosis Factor Signaling in Mesenchymal Stem Cell-Based Therapy for Autoimmune and Inflammatory Diseases

“…Similar effects have been observed on MSCs derived from patients with autoimmune diseases. For instance, it has been shown that TNF treatment decreased the HGF production by BM-MSCs derived from SLE patients via the TNFR1/IKK-β pathway ( 80 ) and induced apoptosis in BM-MSCs from ankylosing spondylitis patients via TNFR1-mediated upregulation of TRAIL-R2 ( 133 ).…”