Identification of the CXCL12–CXCR4/CXCR7 axis as a potential therapeutic target for immunomodulating macrophage polarization and foreign body response to implanted biomaterials

Abstract

Host recognition and immune-mediated foreign body response (FBR) to biomaterials can compromise the performance of implanted medical devices. Macrophage participation and polarization play vital roles in regulating the development of FBR; therefore, research is ongoing to use macrophages to regulate FBR. At the implantation site, the chemokine CXC chemokine ligand 12 (CXCL12) is upregulated and mediates the recruitment of innate immune cells (e.g., macrophages and monocytes) that participate in FBR. In this study, polymethyl methacrylate (PMMA) was used to induce FBR in vivo. The results indicated that PMMA induced macrophage M1 polarization, both in vitro and in vivo. The expression of CXC chemokine receptor type 7 (CXCR7), the receptor of CXCL12, was significantly higher on macrophages following PMMA implantation. In contrast, the expression of CXCR4 (another receptor of CXCL12) was significantly lower. The inhibition of CXCR7 and promotion of CXCR4 led to macrophage polarization switching from the M1 to M2 phenotype and prominent restriction of FBR. In terms of mechanism, Western blot results showed that STAT1/3/6, ERK1/2, p38 and NF-κB signaling pathways participated in the complex mechanism by which the CXCL12–CXCR4/CXCR7 axis mediated macrophage polarization. Overall, our results demonstrate that targeting the CXCL12–CXCR4/CXCR7 axis may allow for a more selective method of immunomodulating FBR, improving biomaterial biocompatibility without the need for broad immunosuppression.