Monocyte Chemotactic Protein-1 Promotes Inflammatory Vascular Repair of Murine Carotid Aneurysms via a Macrophage Inflammatory Protein-1α and Macrophage Inflammatory Protein-2–Dependent Pathway

Abstract

Background Up to 5% of the population may have a brain aneurysm, and if the brain aneurysm ruptures, there is greater than 50% mortality, and more than onethird of survivors are dependent. Brain aneurysms detected before rupture can be treated to prevent rupture, or ruptured aneurysms can be treated to prevent re-rupture. Endovascular coiling of brain aneurysms is the treatment of choice for some aneurysms; however, up to one quarter of aneurysms may recur. The coiled aneurysms that do not recur are characterized by inflammatory intra-aneurysmal tissue healing; therefore, we studied the biology of this process, specifically, the role of monocyte chemotactic protein-1 (MCP-1), a cytokine known for tissue healing. Methods and Results We created coils with a PLGA coating that released MCP-1 at 3 different doses (100 μg/mL; 1 mg/mL; and 10 mg/mL) and performed a dose-response study for effect on intra-aneurysmal tissue healing in a murine carotid aneurysm model. We then demonstrated MCP-1(100 μg/mL)-releasing coils promote significantly greater aneurysm tissue ingrowth than bare platinum or PLGA-only coils. We show that MCP-1 recruits the migration of fibroblasts, macrophages, smooth muscle cells, and endothelial cells in vitro, in cell migration assays; and in vivo, in murine carotid aneurysms. Using gfp bone marrow transplant chimeric mice, we demonstrate that the MCP-1-recruited fibroblasts and macrophages are derived from the bone marrow. We demonstrate that this MCP-1-mediated vascular inflammatory repair occurs via amacrophage inflammatory protein-1α (MIP-1α) and macrophage inflammatory protein-2 (MIP-2)-dependent pathway. MCP-1 released from coiled murine aneurysms causes significant upregulation of MIP-1α and MIP-2 expression by cytokine array assay. Blocking MIP-1α and MIP-2 with antagonist antibody causes significant decrease in MCP-1-mediated intra-aneurysmal tissue healing. Conclusions Our findings suggest that MCP-1 has a critical role in promoting inflammatory intra-aneurysmal tissue healing in a MIP-1α and MIP-2-dependent pathway.

MCP-1-induced ERK/GSK-3β/Snail signaling facilitates the epithelial–mesenchymal transition and promotes the migration of MCF-7 human breast carcinoma cells

“…30 MCP-1 is one of the key chemokines of the C-C chemokine family that regulate the migration and infiltration of macrophages. 31 In the present study, we have shown that the MCP-1-induced EMT of MCF-7 breast carcinoma cells is tightly correlated with accelerated wound healing and enhanced cell migration and invasion. We demonstrated that MCP-1-stimulated tumorigenic signaling with repressed expression of E-cadherin and upregulated expression of vimentin and fibronectin.…”

Comprehensive analysis of inflammatory markers in chronic thromboembolic pulmonary hypertension patients

“…Thus, local IP-10 may attract fibroblasts from the adventitia or perhaps circulating fibrocytes into the thromboembolic material leading to a persistent accumulation of those cells that secrete collagen and may cause growth and stiffening of this endovascular material. Also MCP-1, MlP1a and IL-6 were shown to promote migration of monocytes, macrophages and fibroblasts [26,27]. Furthermore, MCP-1-induced inflammation can lead to neointimal hyperplasia [28,29] and also stimulates fibroblast proliferation and collagen secretion [30].…”

Immunosuppressive Drug Azathioprine Reduces Aneurysm Progression Through Inhibition of Rac1 and c-Jun-Terminal-N-Kinase in Endothelial Cells

“…In mice, MCP1 is important for the attraction of monocytes, which clearly aggravates aneurysm pathology, but it also plays a role in tissue repair, which alleviates aneurysm development. 9,37,38 Interestingly, the role of CCL5 is more apparent because recently, Iida et al 39 showed in 2 different AAA mouse models that inhibition of CCL5 prevented AAA development and progression. In addition, a polymorphism has been described for the receptor of CCL5 (CCR5 Δ32 deletion) that correlates with aneurysm formation in 2 of 3 human studies, [40][41][42] which suggests an active role for CCL5 in the human aneurysm.…”