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.