Modulation of biomaterial-induced foreign body response by regulating the differentiation and migration of Treg cells through the CXCL12–CXCR4/7 axis†

Abstract

Tissue exposure to implanted biomaterials triggers a foreign body response (FBR), which is a stepwise immunological process involving innate immune cells and tissue repair cells. Although the regulatory T (Treg) cells play a crucial role in inflammation and tissue repair, their function in the process of FBR has not been well investigated. In this study, as titanium (Ti) exhibits better biocompatibility and induces milder FBR than polymethyl methacrylate (PMMA), we analyzed the characteristics of Treg cells during FBR caused by the two types of biomaterials. In a rat femur implantation model, we found that the number of Treg cells around titanium implants was much more than that in the PMMA-implanted group. Meanwhile, the expression of CXCR4 in tissues around Ti implants was significantly higher, and the expression of CXCR7 was lower. When co-cultured with biomaterials and macrophages, the differentiation and migration of Treg cells in the Ti-implanted group were promoted, and this effect could be modulated by CXCR4/7 inhibitors. Moreover, targeting CXCR4/7 influenced the amount of Treg cells in vivo and then reversed the FBR induced by PMMA or Ti implants. In summary, our findings revealed the role of CXCR4/CXCR7 in regulating the migration and differentiation of Treg cells during FBR and suggested that the CXCL12–CXCR4/CXCR7 axis may serve as a potential therapeutic target for immunomodulating foreign body response.