Tsukui Daisuke, Kimura Yoshitaka, Kono Hajime
Department of Internal Medicine, Teikyo University School of Medicine, Tokyo 173-8605, Japan.
Department of Microbiology and Immunology, Teikyo University School of Medicine, Tokyo 173-8605, Japan.
iScience. 2023 Jul 11;26(8):107293. doi: 10.1016/j.isci.2023.107293. eCollection 2023 Aug 18.
Atherosclerosis complicates chronic inflammatory diseases, such as rheumatoid arthritis and systemic lupus erythematosus, suggesting that a shared physiological pathway regulates inflammatory responses in these diseases wherein spleen tyrosine kinase (SYK) is involved. We aimed to identify a shared therapeutic target for atherosclerosis and inflammatory diseases. We used -knockout atherosclerosis-prone mice to determine whether SYK is involved in atherosclerosis via the inflammatory response and elucidate the mechanism of SYK signaling. The -knockout mice showed reduced atherosclerosis , and macrophages derived from this strain showed ameliorated cell migration . CD11c expression decreased on -knockout monocytes and macrophages; it was upregulated by forkhead box protein O1 (FOXO1) after stimulation with granulocyte-macrophage colony-stimulating factor (GM-CSF), and c-Jun amino-terminal kinase (JNK) mediated SYK signaling to FOXO1. Furthermore, FOXO1 inhibitor treatment mitigated atherosclerosis in mice. Thus, GM-CSF receptor/SYK/JNK/FOXO1/CD11c signaling in monocytes and macrophages and FOXO1 could be therapeutic targets for atherosclerosis and inflammatory diseases.
动脉粥样硬化会使慢性炎症性疾病（如类风湿性关节炎和系统性红斑狼疮）复杂化，这表明存在一条共同的生理途径来调节这些疾病中的炎症反应，其中脾酪氨酸激酶（SYK）参与其中。我们旨在确定动脉粥样硬化和炎症性疾病的共同治疗靶点。我们使用基因敲除的动脉粥样硬化易感小鼠来确定SYK是否通过炎症反应参与动脉粥样硬化，并阐明SYK信号传导的机制。基因敲除小鼠的动脉粥样硬化程度降低，并且源自该品系的巨噬细胞的细胞迁移得到改善。基因敲除的单核细胞和巨噬细胞上的CD11c表达降低；在用粒细胞-巨噬细胞集落刺激因子（GM-CSF）刺激后，叉头框蛋白O1（FOXO1）使其上调，并且c-Jun氨基末端激酶（JNK）介导SYK向FOXO1的信号传导。此外，FOXO1抑制剂治疗减轻了小鼠的动脉粥样硬化。因此，单核细胞和巨噬细胞中的GM-CSF受体/SYK/JNK/FOXO1/CD11c信号传导以及FOXO1可能是动脉粥样硬化和炎症性疾病的治疗靶点。
