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

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    • Isoda Kikuo
    • Division of Cardiology, Juntendo University|Division of Cardiovascular Medicine, Department of Internal Medicine 1, National Defense Medical College
    • Niida Tomiharu
    • Division of Cardiovascular Medicine, Department of Internal Medicine 1, National Defense Medical College
    • Adachi Takeshi
    • Division of Cardiovascular Medicine, Department of Internal Medicine 1, National Defense Medical College
    • Iwakura Yoichiro
    • Research Institute for Biomedical Sciences, Tokyo University of Science


<b><i>Aim</i></b>: 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).<br><b><i>Methods</i></b>: 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<sup>WT→WT </sup>(<i>n</i>=12), BMT<sup>Ra-/-→WT</sup> (<i>n</i>=12), BMT<sup>WT→Ra-/-</sup> (<i>n</i>=12) and BMT<sup>Ra-/-→Ra-/-</sup> (<i>n</i>=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.<br><b><i>Results</i></b>: Neointimal formation was decreased in the BMT<sup>WT→Ra-/-</sup> mice compared with that observed in the BMT<sup>Ra-/-→Ra-/-</sup> mice (<i>p</i><0.001), but significantly more so in the BMT<sup>Ra-/-→WT</sup> (<i>p</i><0.01) and BMT<sup>WT→WT</sup> (<i>p</i><0.01) mice. In contrast, the neointimal formation in the BMT<sup>Ra-/-→WT</sup> mice was significantly increased compared with that noted in the BMT<sup>WT→WT</sup> mice (<i>p</i><0.05). In addition, immunostaining revealed that Mac3-positive areas were significantly increased in the BMT<sup>Ra-/-→Ra-/-</sup> mice compared with those seen in the other three groups (<i>p</i><0.001), with a significantly decreased percentage of alpha-SMA-positive areas in the neointima in the BMT<sup>Ra-/-→Ra-/-</sup> mice compared with that found in the remaining groups (<i>p<</i>0.001). Furthermore, IL-1Ra staining demonstrated the IL-1Ra expression in several inflammatory cells in the adventitia in the BMT<sup>WT→WT</sup> and BMT<sup>WT→Ra-/-</sup> mice, compared to the neointima in the BMT<sup>WT→WT</sup> and BMT<sup>Ra-/-→WT</sup> mice.<br><b><i>Conclusions</i></b>: 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.


  • Journal of Atherosclerosis and Thrombosis

    Journal of Atherosclerosis and Thrombosis 21(11), 1208-1218, 2014

    Japan Atherosclerosis Society


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