Monocyte Chemotactic Protein-1–Interleukin-6–Osteopontin Pathway of Intra-Aneurysmal Tissue Healing

Abstract

Background and Purpose— We have previously demonstrated that the local delivery of monocyte chemotactic protein-1 (MCP-1) via an MCP-1–releasing poly(lactic-co-glycolic acid)–coated coil promotes intra-aneurysmal tissue healing. In this study, we demonstrate that interleukin-6 (IL-6) and osteopontin are downstream mediators in the MCP-1–mediated aneurysm-healing pathway. Methods— Murine carotid aneurysms were created in C57BL/6 mice. Drug-releasing coils (MCP-1, IL-6, and osteopontin) and control poly(lactic-co-glycolic acid) coils were created and then implanted into the aneurysms to evaluate their intra-aneurismal–healing capacity. To investigate the downstream mediators for aneurysm healing, blocking antibodies for IL-6 receptor and osteopontin were given to the mice implanted with the MCP-1–releasing coils. A histological analysis of both murine and human aneurysms was utilized to cross-validate the data. Results— We observed increased expression of IL-6 in MCP-1-coil–treated aneurysms and not in control-poly(lactic-co-glycolic acid)-only–treated aneurysms. MCP-1–mediated intra-aneurysmal healing is inhibited in mice given blocking antibody to IL-6 receptor. MCP-1–mediated intra-aneurysmal healing is also inhibited by blocking antibody to osteopontin. The role of IL-6 in intra-aneurysmal healing is in recruiting of endothelial cells and fibroblasts. Local delivery of osteopontin to murine carotid aneurysms via osteopontin-releasing coil significantly promotes intra-aneurysmal healing, but IL-6–releasing coil does not, suggesting that IL-6 cannot promote aneurysm healing independent of MCP-1. In the MCP-1–mediated aneurysm healing, osteopontin expression is dependent on IL-6; inhibition of IL-6 receptor significantly inhibits osteopontin expression in MCP-1–mediated aneurysm healing. Conclusions— Our findings suggest that IL-6 and osteopontin are key downstream mediators of MCP-1–mediated intra-aneurysmal healing.