Additive Therapeutic Effects of Mesenchymal Stem Cells and IL-37 for Systemic Lupus Erythematosus

• Published in: Journal of the American Society of Nephrology Vol. 31; no. 1; pp. 54 - 65
• Main Authors: Xu, Jianyong, Chen, Jieting, Li, Wenlei, Lian, Wei, Huang, Jieyong, Lai, Baoyu, Li, Lingyun, Huang, Zhong
• Format: Journal Article
• Language: English
• Published: United States American Society of Nephrology 01.01.2020
• Subjects: Animals; Basic Research; Cells, Cultured; Combined Modality Therapy; Female; Interleukin-1 - biosynthesis; Interleukin-1 - therapeutic use; Lupus Erythematosus, Systemic - therapy; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells - metabolism; Mice; Mice, Inbred MRL lpr; interleukin-37; IL-37; MSCs; systemic lupus erythematosus; SLE; mesenchymal stem cells
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/ASN.2019050545

Although mesenchymal stem cells (MSCs) might offer a promising strategy for treating SLE, their immunoregulatory plasticity makes their therapeutic effects unpredictable. Whether overexpressing IL-37, an IL-1 family member with immunosuppressive activity, might enhance the therapeutic effects of these cells for SLE is unknown. We genetically modified MSCs to overexpress IL-37 and assessed their effects on immune suppression . We also evaluated the effects of such cells versus effects of various controls after transplanting them into MRL/ mice (model of SLE). Stem cell characteristics did not appear altered in MSCs overexpressing IL-37. These cells had enhanced immunosuppression in terms of inhibiting splenocyte proliferation, reducing proinflammatory factors (IL-1 , TNF- , IL-17, and IL-6), and suppressing autoantibodies (anti-dsDNA and anti-ANA). Compared with animals receiving control MSCs or IL-37 treatment alone, MRL/ mice transplanted with IL-37-overexpressing cells displayed improved survival and reduced signs of SLE (indicated by urine protein levels, spleen weight, and renal pathologic scores); they also had significantly lower expression of proinflammatory factors, lower total antibody levels in serum and urine, lower autoantibody production, and showed reduced T cell numbers in the serum and kidney. Expression of IL-37 by MSCs can maintain higher serum levels of IL-37, and MSCs had prolonged survival after transplantation, perhaps through IL-37 suppressing the inflammatory microenvironment. Mutually reinforcing interaction between MSCs and IL-37 appears to underlie their additive therapeutic effects. Genetic modification to overexpress IL-37 might offer a way to enhance the stability and effectiveness of MSCs in treating SLE.