Interleukin‐38 suppresses abdominal aortic aneurysm formation in mice by regulating macrophages in an <scp>IL1RL2</scp>‐p38 pathway‐dependent manner

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  • Shun Kurose
    Department of Surgery and Science, Graduate School of Medical Sciences Kyushu University Fukuoka Japan
  • Yutaka Matsubara
    Department of Surgery and Science, Graduate School of Medical Sciences Kyushu University Fukuoka Japan
  • Shinichiro Yoshino
    Department of Surgery and Science, Graduate School of Medical Sciences Kyushu University Fukuoka Japan
  • Keiji Yoshiya
    Department of Kidney Center Saiseikai Yahata General Hospital Fukuoka Japan
  • Koichi Morisaki
    Department of Surgery and Science, Graduate School of Medical Sciences Kyushu University Fukuoka Japan
  • Tadashi Furuyama
    Department of Surgery and Science, Graduate School of Medical Sciences Kyushu University Fukuoka Japan
  • Tomoaki Hoshino
    Division of Respirology, Neurology and Rheumatology, Department of Medicine Kurume University School of Medicine Fukuoka Japan
  • Tomoharu Yoshizumi
    Department of Surgery and Science, Graduate School of Medical Sciences Kyushu University Fukuoka Japan

抄録

<jats:title>Abstract</jats:title><jats:p>Macrophages play crucial roles in abdominal aortic aneurysm (AAA) formation through the inflammatory response and extracellular matrix degradation; therefore, regulating macrophages may suppress AAA formation. Interleukin‐38 (IL‐38) is a member of the IL‐1 family, which binds to IL‐36 receptor (IL1RL2) and has an anti‐inflammation effect. Because macrophages express IL1RL2, we hypothesized that IL‐38 suppresses AAA formation by controlling macrophages. We assessed a C57BL6/J mouse angiotensin II‐induced AAA model with or without IL‐38 treatment. RAW 264.7 cells were cultured with tumor necrosis factor‐α and treated with or without IL‐38. Because p38 has important roles in inflammation, we assessed p38 phosphorylation in vitro and in vivo. To clarify whether the IL‐38 effect depends on the p38 pathway, we used SB203580 to inhibit p38 phosphorylation. IL1RL2<jats:sup>+</jats:sup> macrophage accumulation along with matrix metalloproteinase (MMP)‐2 and ‐9 expression was observed in mouse AAA. IL‐38 reduced the incidence of AAA formation along with reduced M1 macrophage accumulation and MMP‐2 and ‐9 expression in the AAA wall. Macrophage activities including inducible nitric oxide, MMP‐2, and MMP‐9 production and spindle‐shaped changes were significantly suppressed by IL‐38. Furthermore, we revealed that inhibition of p38 phosphorylation diminished the effects of IL‐38 on regulating macrophages to reduce AAA incidence, indicating the protective effects of IL‐38 depend on the p38 pathway. IL‐38 plays protective roles against AAA formation through regulation of macrophage accumulation in the aortic wall and modulating the inflammatory phenotype. Using IL‐38 may be a novel therapy for AAA patients.</jats:p>

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