M2 macrophages induced by mesenchymal stem cells provide an anti-inflammatory milieu that induces regulatory T cells in collagen-induced mice

Abstract

Objective: Mesenchymal stem cells (MSCs) have immunomodulatory properties. Previous studies have shown the therapeutic effects of MSCs in collagen-induced arthritis (CIA) mice and suggested mechanisms underlying the effects of MSC treatment, including the induction of regulatory T cells (Tregs). Many clinical trials for inflammatory diseases are underway; however, the host immune response to MSCs is not fully understood. Herein, the immunomodulatory properties of human MSCs in macrophages in CIA mice and the mechanism by which MSCs affect macrophages were investigated. Methods: CIA was induced in DBA/1J mice. Human adipose-derived (hAD)-MSCs were intraperitoneally injected, and the therapeutic efficacy of hAD-MSCs in CIA mice was evaluated. Peritoneal macrophages (PM) and splenic T cells were also analyzed. Macrophages isolated from DBA/1J mice were co-cultured with hAD-MSCs, and macrophage polarization and cytokine expression were analyzed by FACS and ELISA. Protein and mRNA expression levels were examined by western blot and qPCR. Results: hAD-MSCs ameliorated the severity of disease in CIA mice by inducing M2 macrophages in the peritoneum. The emergence of M2 macrophages preceded that of Tregs in CIA mice. hAD-MSCs enhanced IL-10 and TGF-β1 expression in M2 macrophages. Moreover, hAD-MSCs decreased RAGE and NF-κB expression, but increased STAT6 expression. STAT5 gene expression in macrophages decreased. Conclusion: The results showed that hAD-MSCs exerted therapeutic effects by inducing M2 macrophages in CIA mice. hAD-MSCs reduced RAGE and NF-κB expression and modulated the STAT family of macrophages. IL-10 and TGF-β1 produced by the induced M2 macrophages might result in an anti-inflammatory milieu that induces Tregs.