研究领域：心血管疾病 免疫学 分子生物学

关键字：CXCL14 动脉粥样硬化发生 泡沫细胞 THP-1 氧化低密度脂蛋白 AP-1 ERK1/2通路 动脉粥样硬化 免疫疗法 ApoE −/− 小鼠

CXC趋化因子家族长期以来被认为与动脉粥样硬化发生相关。然而，CXCL14与动脉粥样硬化发生之间的关系尚不明确。本研究通过免疫组织化学方法初步检测了动脉粥样硬化标本中泡沫细胞内CXCL14的表达。体外泡沫细胞由THP-1细胞经佛波醇-12-十四烷酰-13-乙酸酯（PMA）及氧化型低密度脂蛋白（ox-LDL）刺激诱导生成。免疫印迹（Immunoblotting）与定量PCR（qPCR）证实CXCL14在泡沫细胞形成过程中表达发生显著变化。进一步研究表明，ox-LDL通过AP-1调控CXCL14表达；AP-1可结合于CXCL14启动子区并上调其mRNA表达水平。此外，CXCL14主要通过ERK1/2信号通路促进THP-1细胞迁移、巨噬细胞脂质吞噬作用以及平滑肌细胞迁移与增殖。另外，在ApoE−/−小鼠模型中，CXCL14多肽诱导的免疫治疗显示出显著疗效。综上所述，本研究证实CXCL14在泡沫细胞形成过程中显著上调，并以多种机制促进动脉粥样硬化发生发展；CXCL14有望成为动脉粥样硬化的潜在治疗靶点。CXC chemokine family has been related to atherogenesis for long. However, the relationship between CXCL14 and atherogenesis is still unclear. This study preliminarily detected CXCL14 expression at foam cells in atherosclerosis specimens by immunohistochemistry. In vitro foam cells were derived from THP-1 after phorbol-12-myristate-13-acetate (PMA) and oxidized low-density lipoprotein (ox-LDL) stimulation. Immunoblotting and qPCR convinced CXCL14 expression variation during foam cell formation. We further demonstrated that ox-LDL regulated CXCL14 expression by AP-1. AP-1 could bind to CXCL14 promoter and up-regulate CXCL14 mRNA expression. Besides, CXCL14 promoted THP-1 migration, macrophage lipid phagocytosis, and smooth muscle cell migration as well as proliferation mainly via the ERK1/2 pathway. Additionally, a CXCL14 peptide-induced immune therapy showed efficacy in ApoE^−/− mouse model. In conclusion, our study demonstrated that CXCL14 is highly up-regulated during foam cell formation and promotes atherogenesis in various ways. CXCL14 may be a potent therapeutic target for atherosclerosis.