sTNFRII-Fc modification protects human UC-MSCs against apoptosis/autophagy induced by TNF-alpha and enhances their efficacy in alleviating inflammatory arthritis

Background: Tumor necrosis factor (TNF)-alpha inhibitors represented by Etanercept (a fusion protein containing soluble TNF receptor II (sTNFRII) and the Fc segment of human IgG1) play a pivotal role in Rheumatoid arthritis (RA) treatment. However, long-term use increases the risk of infection and tumors for their systemic inhibition of TNF-alpha, which disrupts the regular physiological function of this molecular. Mesenchymal stem cells (MSCs)-based delivery system provides new options for RA treatment with their homing and immune-regulation capacities, whereas inflammatory environment (especially TNF-alpha) is not conducive to MSCs' therapeutic effects by inducing apoptosis/autophagy. Here, we constructed a strain of sTNFRII-Fc-expressing MSCs (sTNFRII-MSC), aiming to offset the deficiency of those two interventions. Methods: Constructed sTNFRII-Fc lentiviral vector was used to infect human umbilical cord-derived MSCs, and sTNFRII-MSC stable cell line was generated by monoclonal cultivation. In vitro and vivo characteristics of sTNFRII-MSC were assessed by coculture assay and an acute inflammatory model in NOD/SCID mice. The sTNFRII-MSC were transplanted into CIA model, pathological and immunological indicators were detected to evaluate the therapeutic effects of sTNFRII-MSC. The distribution of sTNFRII-MSC was determined by immunofluorescence assay. Apoptosis and autophagy were analyzed by flow cytometry, western blot and immunofluorescence. Results: sTNFRII-Fc secreted by sTNFRII-MSC present biological activity both in vitro and vivo. sTNFRII-MSC transplantation effectively alleviates mice collagen-induced arthritis (CIA) via migrating to affected area, protecting articular cartilage destruction, modulating immune balance and sTNFRII-MSC showed prolonged internal retention via resisting apoptosis/autophagy induced by TNF-alpha. Conclusion: sTNFRII-Fc modification protects MSCs against apoptosis/autophagy induced by TNF-alpha, in addition to releasing sTNFRII-Fc neutralizing TNF-alpha to block relevant immune-inflammation cascade, and thus exert better therapeutic effects in alleviating inflammatory arthritis.

Automated summary

The modification of MSCs with sTNFRII-Fc shows promising therapeutic effects in treating rheumatoid arthritis by resisting apoptosis/autophagy induced by TNF-alpha and neutralizing TNF-alpha to block immune-inflammation cascade.