Deletion of Talin1 in Myeloid Cells Facilitates Atherosclerosis in Mice.

IF 7.4 1区 医学 Q1 HEMATOLOGY Arteriosclerosis, Thrombosis, and Vascular Biology Pub Date : 2024-08-01 Epub Date: 2024-06-20 DOI:10.1161/ATVBAHA.123.319677
Huiping Shi, Jianhua Song, Liang Gao, Xindi Shan, Sumith R Panicker, Longbiao Yao, Michael McDaniel, Meixiang Zhou, Samuel McGee, Hui Zhong, Courtney T Griffin, Lijun Xia, Bojing Shao
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Abstract

Background: Integrin-regulated monocyte recruitment and cellular responses of monocyte-derived macrophages are critical for the pathogenesis of atherosclerosis. In the canonical model, talin1 controls ligand binding to integrins, a prerequisite for integrins to mediate leukocyte recruitment and induce immune responses. However, the role of talin1 in the development of atherosclerosis has not been studied. Our study investigated how talin1 in myeloid cells regulates the progression of atherosclerosis.

Methods: On an Apoe-/- background, myeloid talin1-deficient mice and the control mice were fed with a high-fat diet for 8 or 12 weeks to induce atherosclerosis. The atherosclerosis development in the aorta and monocyte recruitment into atherosclerotic lesions were analyzed.

Results: Myeloid talin1 deletion facilitated the formation of atherosclerotic lesions and macrophage deposition in lesions. Talin1 deletion abolished integrin β2-mediated adhesion of monocytes but did not impair integrin α4β1-dependent cell adhesion in a flow adhesion assay. Strikingly, talin1 deletion did not prevent Mn2+- or chemokine-induced activation of integrin α4β1 to the high-affinity state for ligands. In an in vivo competitive homing assay, monocyte infiltration into inflamed tissues was prohibited by antibodies to integrin α4β1 but was not affected by talin1 deletion or antibodies to integrin β2. Furthermore, quantitative polymerase chain reaction and ELISA (enzyme-linked immunosorbent assay) analysis showed that macrophages produced cytokines to promote inflammation and the proliferation of smooth muscle cells. Ligand binding to integrin β3 inhibited cytokine generation in macrophages, although talin1 deletion abolished the negative effects of integrin β3.

Conclusions: Integrin α4β1 controls monocyte recruitment during atherosclerosis. Talin1 is dispensable for integrin α4β1 activation to the high-affinity state and integrin α4β1-mediated monocyte recruitment. Yet, talin1 is required for integrin β3 to inhibit the production of inflammatory cytokines in macrophages. Thus, intact monocyte recruitment and elevated inflammatory responses cause enhanced atherosclerosis in talin1-deficient mice. Our study provides novel insights into the roles of myeloid talin1 and integrins in the progression of atherosclerosis.

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髓系细胞中Talin1的缺失会促进小鼠动脉粥样硬化
背景:整合素调控的单核细胞募集和单核细胞衍生巨噬细胞的细胞反应对动脉粥样硬化的发病机制至关重要。在典型模型中,talin1 控制配体与整合素的结合,这是整合素介导白细胞募集和诱导免疫反应的先决条件。然而,talin1 在动脉粥样硬化发展过程中的作用尚未得到研究。我们的研究探讨了骨髓细胞中的 talin1 如何调控动脉粥样硬化的进展:方法:在载脂蛋白/-背景下,用高脂肪饮食喂养髓系 talin1 基因缺陷小鼠和对照组小鼠 8 或 12 周,诱导动脉粥样硬化。结果表明,髓系talin1缺失小鼠的动脉粥样硬化发生率和单核细胞在动脉粥样硬化病变中的招募率均高于对照组小鼠:结果:髓样talin1缺失促进了动脉粥样硬化病变的形成和病变中巨噬细胞的沉积。在流动粘附试验中,Talin1缺失会削弱整合素β2介导的单核细胞粘附,但不会损害整合素α4β1依赖的细胞粘附。令人震惊的是,talin1 基因缺失并不能阻止 Mn2+ 或趋化因子诱导的整合素 α4β1 对配体高亲和力状态的激活。在体内竞争性归巢试验中,整合素α4β1抗体可阻止单核细胞渗入炎症组织,而缺失滑蛋白1或整合素β2抗体则不会影响单核细胞渗入炎症组织。此外,定量聚合酶链反应和酶联免疫吸附分析表明,巨噬细胞产生的细胞因子可促进炎症和平滑肌细胞的增殖。与整合素β3结合的配体可抑制巨噬细胞中细胞因子的产生,尽管缺失 talin1 可消除整合素β3的负面影响:结论:整合素α4β1控制着动脉粥样硬化过程中单核细胞的募集。整合素α4β1活化到高亲和性状态以及整合素α4β1介导的单核细胞募集都离不开Talin1。然而,整合素 β3 抑制巨噬细胞产生炎症细胞因子需要 Talin1。因此,完整的单核细胞募集和炎症反应的升高会导致缺乏 talin1 的小鼠动脉粥样硬化加重。我们的研究为了解髓系 talin1 和整合素在动脉粥样硬化进展中的作用提供了新的视角。
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来源期刊
CiteScore
15.60
自引率
2.30%
发文量
337
审稿时长
2-4 weeks
期刊介绍: The journal "Arteriosclerosis, Thrombosis, and Vascular Biology" (ATVB) is a scientific publication that focuses on the fields of vascular biology, atherosclerosis, and thrombosis. It is a peer-reviewed journal that publishes original research articles, reviews, and other scholarly content related to these areas. The journal is published by the American Heart Association (AHA) and the American Stroke Association (ASA). The journal was published bi-monthly until January 1992, after which it transitioned to a monthly publication schedule. The journal is aimed at a professional audience, including academic cardiologists, vascular biologists, physiologists, pharmacologists and hematologists.
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