Abstract：
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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 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.
UNASSIGNED: 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.
摘要：
■整合素调节的单核细胞募集和单核细胞衍生的巨噬细胞的细胞反应对于动脉粥样硬化的发病机理至关重要。在规范模型中，talin1控制配体与整合素的结合，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中的作用尚未被研究。我们的研究调查了骨髓细胞中的距蛋白1如何调节动脉粥样硬化的进展。
■在Apo-/-背景下，用高脂饮食喂养髓样距1缺陷小鼠和对照小鼠8或12周以诱导动脉粥样硬化。分析主动脉中的动脉粥样硬化发展和单核细胞募集成动脉粥样硬化病变。
■髓样距骨蛋白1缺失促进了动脉粥样硬化病变的形成和巨噬细胞在病变中的沉积。Talin1缺失消除了整合素β2介导的单核细胞粘附，但在流动粘附测定中并未损害整合素α4β1依赖性细胞粘附。引人注目的是，talin1缺失并不能阻止Mn2-或趋化因子诱导的整合素α4β1活化为配体的高亲和力状态。在体内竞争性归巢试验中，整合素α4β1的抗体阻止单核细胞向发炎组织的浸润，但不受talin1缺失或整合素β2抗体的影响。此外，定量聚合酶链反应和ELISA分析显示巨噬细胞产生细胞因子促进炎症反应和平滑肌细胞增殖。与整合素β3结合的配体抑制了巨噬细胞中细胞因子的产生，尽管talin1缺失消除了整合素β3的负面影响。
■整合素α4β1控制动脉粥样硬化期间的单核细胞募集。Talin1对于整联蛋白α4β1活化成高亲和力状态和整联蛋白α4β1介导的单核细胞募集是不必要的。然而，整合素β3需要talin1来抑制巨噬细胞中炎性细胞因子的产生。因此，完整的单核细胞募集和升高的炎症反应导致talin1缺陷小鼠动脉粥样硬化增强。我们的研究提供了有关髓样距蛋白1和整合素在动脉粥样硬化进展中的作用的新见解。
■在Apo-/-背景下，用高脂饮食喂养髓样距1缺陷小鼠和对照小鼠8或12周以诱导动脉粥样硬化。分析主动脉中的动脉粥样硬化发展和单核细胞募集成动脉粥样硬化病变。
■髓样距骨蛋白1缺失促进了动脉粥样硬化病变的形成和巨噬细胞在病变中的沉积。Talin1缺失消除了整合素β2介导的单核细胞粘附，但在流动粘附测定中并未损害整合素α4β1依赖性细胞粘附。引人注目的是，talin1缺失并不能阻止Mn2-或趋化因子诱导的整合素α4β1活化为配体的高亲和力状态。在体内竞争性归巢试验中，整合素α4β1的抗体阻止单核细胞向发炎组织的浸润，但不受talin1缺失或整合素β2抗体的影响。此外，定量聚合酶链反应和ELISA分析显示巨噬细胞产生细胞因子促进炎症反应和平滑肌细胞增殖。与整合素β3结合的配体抑制了巨噬细胞中细胞因子的产生，尽管talin1缺失消除了整合素β3的负面影响。
■整合素α4β1控制动脉粥样硬化期间的单核细胞募集。Talin1对于整联蛋白α4β1活化成高亲和力状态和整联蛋白α4β1介导的单核细胞募集是不必要的。然而，整合素β3需要talin1来抑制巨噬细胞中炎性细胞因子的产生。因此，完整的单核细胞募集和升高的炎症反应导致talin1缺陷小鼠动脉粥样硬化增强。我们的研究提供了有关髓样距蛋白1和整合素在动脉粥样硬化进展中的作用的新见解。
