Latexin deficiency limits foam cell formation and ameliorates atherosclerosis by promoting macrophage phenotype differentiation.

IF 8.1 1区 生物学 Q1 CELL BIOLOGY
Guozhang He, Yuanting Ni, Rong Hua, Huaibin Wan, Yanhui Tan, Qiwei Chen, Shaohua Xu, Yuzhong Yang, Lijun Zhang, Wei Shu, Ke-Bin Huang, Yi Mo, Hong Liang, Ming Chen
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Abstract

Latexin (LXN) is abundant in macrophages and plays critical roles in inflammation. Much is known about macrophages in atherosclerosis, the role of macrophage LXN in atherosclerosis has remained elusive. Here, the expression of LXN in human and mouse atherosclerotic lesions was examined by immunofluorescence and immunohistochemistry. LXN knockout and LXN/ApoE double-knockout mice were generated to evaluate the functions of LXN in atherosclerosis. Bone marrow transplantation (BMT) experimentation was carried out to determine whether macrophage LXN regulates atherosclerosis. We found that LXN is enriched in human and murine atherosclerotic lesions, mainly localized to macrophages. LXN deletion ameliorated atherosclerosis in ApoE-/- mice. BMT demonstrate that deletion of LXN in bone marrow protects ApoE-/- mice against atherosclerosis. Mechanistically, we found that LXN targets and inhibits JAK1 in macrophages. LXN deficiency stimulates the JAK1/STAT3/ABC transporter pathway, thereby enhancing the anti-inflammatory and anti-oxidant phenotype, cholesterol efflux, subsequently minimizing foam cell formation and atherosclerosis. Gene therapy by treatment of atherosclerotic mice with adeno-associated virus harbouring LXN-depleting shRNA attenuated the disease phenotype. In summary, our study provides new clues for the role of LXN in the pathological regulation of atherosclerosis, and determines that LXN is a target for preventing atherosclerosis, which may be a potential new anti-atherosclerosis therapeutic target.

缺乏乳清蛋白会限制泡沫细胞的形成,并通过促进巨噬细胞表型分化改善动脉粥样硬化。
Latexin (LXN) 在巨噬细胞中含量丰富,在炎症中发挥着关键作用。人们对巨噬细胞在动脉粥样硬化中的作用已经有了很多了解,但巨噬细胞 LXN 在动脉粥样硬化中的作用却一直难以捉摸。在此,我们通过免疫荧光和免疫组织化学方法研究了人和小鼠动脉粥样硬化病变中 LXN 的表达。为了评估LXN在动脉粥样硬化中的功能,研究人员培育了LXN基因敲除小鼠和LXN/ApoE双基因敲除小鼠。我们还进行了骨髓移植(BMT)实验,以确定巨噬细胞 LXN 是否调控动脉粥样硬化。我们发现,LXN在人类和小鼠动脉粥样硬化病变中富集,主要定位于巨噬细胞。删除 LXN 可改善 ApoE-/- 小鼠的动脉粥样硬化。骨髓移植证明,在骨髓中缺失 LXN 可保护载脂蛋白 E-/- 小鼠免受动脉粥样硬化的侵袭。从机理上讲,我们发现 LXN 靶向并抑制巨噬细胞中的 JAK1。缺乏 LXN 会刺激 JAK1/STAT3/ABC 转运体途径,从而增强抗炎和抗氧化表型以及胆固醇外流,进而最大限度地减少泡沫细胞的形成和动脉粥样硬化。用携带 LXN 缺失 shRNA 的腺相关病毒对动脉粥样硬化小鼠进行基因治疗可减轻疾病表型。总之,我们的研究为 LXN 在动脉粥样硬化病理调控中的作用提供了新的线索,并确定 LXN 是预防动脉粥样硬化的靶点,可能成为潜在的抗动脉粥样硬化治疗新靶点。
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来源期刊
Cell Death & Disease
Cell Death & Disease CELL BIOLOGY-
CiteScore
15.10
自引率
2.20%
发文量
935
审稿时长
2 months
期刊介绍: Brought to readers by the editorial team of Cell Death & Differentiation, Cell Death & Disease is an online peer-reviewed journal specializing in translational cell death research. It covers a wide range of topics in experimental and internal medicine, including cancer, immunity, neuroscience, and now cancer metabolism. Cell Death & Disease seeks to encompass the breadth of translational implications of cell death, and topics of particular concentration will include, but are not limited to, the following: Experimental medicine Cancer Immunity Internal medicine Neuroscience Cancer metabolism
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