IL-37b gene transfer enhances the therapeutic efficacy of mesenchumal stromal cells in DSS-induced colitis mice

Abstract

Aim:To investigate whether the transfer of the IL-37b gene, a newly identified inhibitor of both innate and adaptive immunity, could improve the therapeutic efficacy of mesenchumal stromal cells (MSCs) in inflammatory bowel disease (IBD).Methods:The expression of IL-37 in biopsied specimens of the patients with active ulcerative colitis (UC) was detected using RT-PCR and immunohistochemistry. Mice were treated with 3% dextran sulfate sodium (DSS) for 8 days to induce colitis. Before DSS treatment, the mice were injected with MSCs, MSC-eGFP or MSC-IL37b. Their body weight was measured each day, and the colons and spleens were harvested on d 10 for pathological and biochemical analyses.Results:In biopsied specimens of the patients with active UC, the expression of IL-37 was dramatically elevated in inflamed mucosa, mainly in epithelial cells and infiltrating immune cells. Compared to MSC-eGFP or MSCs, MSC-IL37b administration significantly attenuated the body weight and colon length reduction, and decreased the histological score in DSS-induced colitis mice. Furthermore, MSC-IL37b administration increased the percentage of myeloid-derived suppressor cells (MDSCs) among total splenic mononuclear cells as well as the percentage of regulatory T cells (Tregs) among splenic CD4+ T cells in the mice. Moreover, MSC-IL37b administration increased the IL-2+ cells and decreased the IFN-γ+ cells among splenic CD4+ T cells.Conclusion:IL-37 is involved in the pathophysiology of UC. IL-37b gene transfer enhances the therapeutic efficacy of MSCs in DSS-induced colitis mice by inducing Tregs and MDSCs and regulating cytokine production.

Insights into IL-37, the role in autoimmune diseases

“…MSC-IL-37 treated mice up-regulated the percentage of myeloid-derived suppressor cells (MDSCs) among total splenic mononuclear cells, the percentage of Tregs among splenic CD4+ T cells. Interestingly, MSC-IL-37 administration up-regulated the IL-2 + cells and reduced the IFN-γ + cells among splenic CD4 + T cells, suggesting that IL-37 gene transfer promotes the therapeutic efficacy of MSCs in colitis via inducing Tregs and MDSCs, controlling cytokines production [31].…”

Human mesenchymal stem cells (MSCs) for treatment towards immune- and inflammation-mediated diseases: review of current clinical trials

“…To improve the efficacy of MSC treatment for IBD, these progenitor/stem cells have also been coated with antibodies against mucosal addressin cell adhesion moledule-1 (MAdCAM-1) and vascular cell adhesion molecule-1 (VCAM-1), both of which were shown to increase cell delivery to inflamed intestinal regions [104]. Immunosuppression was also enhanced when MSCs was modified with IL-12p40 or IL-37ß [105, 106]. …”

Recent Advances: The Imbalance of Cytokines in the Pathogenesis of Inflammatory Bowel Disease

“…IL-37b-tg mice protect from DSS-induced colitis, characterized by decreasing clinical disease score, histological score, and TNF α and IL-1 β production, but increasing IL-10 production in colon tissue [99]. If overexpressing IL-37b on mesenchymal stromal cells, it will greatly increase the therapeutic efficacy of mesenchymal stromal cells in DSS-induced murine colitis [100]. These results indicate that IL-37 may be useful for the treatment of IBD.…”