Interleukin-1 Receptor Antagonist Originating from Bone Marrowderived Cells and Non-bone Marrow-derived Cells Helps to Suppress Arterial Inflammation and Reduce Neointimal Formation after Injury

Abstract

AIM: Interleukin-1 receptor antagonist (IL-1Ra) negatively regulates IL-1 signaling by blocking the functional receptor. We previously demonstrated that IL-1Ra-deficient (IL-1Ra-/-) mice exhibit marked neointimal formation after injury. IL-1Ra is expressed on bone marrow (BM)-derived cells as well as non-BM intrinsic arterial cells. However, the importance of various cell types as sources of IL-1Ra remains unknown. The aim of this study was to test the hypothesis that IL-1Ra originating from BM-derived cells and non-BM intrinsic cells helps to suppress both inflammation and neointimal formation after vascular injury using a model of BM cell transplantation (BMT). METHODS: In order to determine the contribution of IL-1Ra-deficient (Ra-/-) and wild-type (WT) BM cells to neointimal formation, we developed four types of BM chimeric mice (BMT(WT→WT) (n=12), BMT(Ra-/-→WT) (n=12), BMT(WT→Ra-/-) (n=12) and BMT(Ra-/-→Ra-/-) (n=12)). At four weeks after BMT, we induced vascular injury by placing a non-occlusive cuff around the femoral artery. Histological analyses were subsequently performed two weeks after injury. RESULTS: Neointimal formation was decreased in the BMT(WT→Ra-/-) mice compared with that observed in the BMT(Ra-/-→Ra-/-) mice (p＜0.001), but significantly more so in the BMT(Ra-/-→WT) (p＜0.01) and BMT(WT→WT) (p＜0.01) mice. In contrast, the neointimal formation in the BMT(Ra-/-→WT) mice was significantly increased compared with that noted in the BMT(WT→WT) mice (p＜0.05). In addition, immunostaining revealed that Mac3-positive areas were significantly increased in the BMT(Ra-/-→Ra-/-) mice compared with those seen in the other three groups (p＜0.001), with a significantly decreased percentage of alpha-SMA-positive areas in the neointima in the BMT(Ra-/-→Ra-/-) mice compared with that found in the remaining groups (p＜0.001). Furthermore, IL-1Ra staining demonstrated the IL-1Ra expression in several inflammatory cells in the adventitia in the BMT(WT→WT) and BMT(WT→Ra-/-) mice, compared to the neointima in the BMT(WT→WT) and BMT(Ra-/-→WT) mice. CONCLUSIONS: The IL-1Ra present in BM-derived cells and non-BM cells helps to suppress arterial inflammation, resulting in decreased neointimal formation after injury. These findings shed new light on the mechanisms underlying the development of atherosclerosis and restenosis after angioplasty.