Monocytes Reprogrammed by 4-PBA Potently Contribute to the Resolution of Inflammation and Atherosclerosis.

IF 16.5 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Circulation research Pub Date : 2024-09-27 Epub Date: 2024-09-03 DOI:10.1161/CIRCRESAHA.124.325023
Shuo Geng, Ran Lu, Yao Zhang, Yajun Wu, Ling Xie, Blake A Caldwell, Kisha Pradhan, Ziyue Yi, Jacqueline Hou, Feng Xu, Xian Chen, Liwu Li
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Abstract

Background: Chronic inflammation initiated by inflammatory monocytes underlies the pathogenesis of atherosclerosis. However, approaches that can effectively resolve chronic low-grade inflammation targeting monocytes are not readily available. The small chemical compound 4-phenylbutyric acid (4-PBA) exhibits broad anti-inflammatory effects in reducing atherosclerosis. Selective delivery of 4-PBA reprogrammed monocytes may hold novel potential in providing targeted and precision therapeutics for the treatment of atherosclerosis.

Methods: Systems analyses integrating single-cell RNA sequencing and complementary immunologic approaches characterized key resolving characteristics as well as defining markers of reprogrammed monocytes trained by 4-PBA. Molecular mechanisms responsible for monocyte reprogramming were assessed by integrated biochemical and genetic approaches. The intercellular propagation of homeostasis resolution was evaluated by coculture assays with donor monocytes trained by 4-PBA and recipient naive monocytes. The in vivo effects of monocyte resolution and atherosclerosis prevention by 4-PBA were assessed with the high-fat diet-fed ApoE-/- mouse model with IP 4-PBA administration. Furthermore, the selective efficacy of 4-PBA-trained monocytes was examined by IV transfusion of ex vivo trained monocytes by 4-PBA into recipient high-fat diet-fed ApoE-/- mice.

Results: In this study, we found that monocytes can be potently reprogrammed by 4-PBA into an immune-resolving state characterized by reduced adhesion and enhanced expression of anti-inflammatory mediator CD24. Mechanistically, 4-PBA reduced the expression of ICAM-1 (intercellular adhesion molecule 1) via reducing peroxisome stress and attenuating SYK (spleen tyrosine kinase)-mTOR (mammalian target of rapamycin) signaling. Concurrently, 4-PBA enhanced the expression of resolving mediator CD24 through promoting PPARγ (peroxisome proliferator-activated receptor γ) neddylation mediated by TOLLIP (toll-interacting protein). 4-PBA-trained monocytes can effectively propagate anti-inflammation activity to neighboring monocytes through CD24. Our data further demonstrated that 4-PBA-trained monocytes effectively reduce atherosclerosis pathogenesis when administered in vivo.

Conclusions: Our study describes a robust and effective approach to generate resolving monocytes, characterizes novel mechanisms for targeted monocyte reprogramming, and offers a precision therapeutics for atherosclerosis based on delivering reprogrammed resolving monocytes.

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经 4-PBA 重编程的单核细胞可有效缓解炎症和动脉粥样硬化。
背景:由炎症单核细胞引发的慢性炎症是动脉粥样硬化发病机制的基础。然而,目前还没有针对单核细胞有效解决慢性低度炎症的方法。小分子化合物 4-苯基丁酸(4-PBA)在减轻动脉粥样硬化方面具有广泛的抗炎作用。选择性递送 4-PBA 重编程单核细胞可能具有新的潜力,为治疗动脉粥样硬化提供靶向和精准治疗:方法:结合单细胞 RNA 测序和互补免疫学方法进行系统分析,确定了 4-PBA 训练的重编程单核细胞的关键分辨特征和定义标记。综合生化和遗传方法评估了单核细胞重编程的分子机制。通过与经 4-PBA 训练的供体单核细胞和受体天真单核细胞进行共培养实验,评估了细胞间平衡解析的传播。在高脂饮食喂养的载脂蛋白E-/-小鼠模型中,通过IP 4-PBA给药,评估了4-PBA在体内解决单核细胞问题和预防动脉粥样硬化的效果。此外,还通过向接受高脂饮食的载脂蛋白E-/-小鼠静脉注射4-PBA训练的单核细胞,检测了4-PBA训练的单核细胞的选择性功效:结果:在这项研究中,我们发现单核细胞可被 4-PBA 有效地重塑为一种以粘附性降低和抗炎介质 CD24 表达增强为特征的免疫溶解状态。从机理上讲,4-PBA 通过降低过氧化物酶体应激和减弱 SYK(脾脏酪氨酸激酶)-mTOR(哺乳动物雷帕霉素靶标)信号传导,减少了 ICAM-1(细胞间粘附分子 1)的表达。与此同时,4-PBA 通过促进由 TOLLIP(通行费互作蛋白)介导的 PPARγ(过氧化物酶体增殖激活受体γ)内酰化,增强了分解介质 CD24 的表达。经过 4-PBA 训练的单核细胞可通过 CD24 向邻近的单核细胞有效传播抗炎活性。我们的数据进一步证明,4-PBA 训练的单核细胞在体内给药时可有效减少动脉粥样硬化的发病机制:我们的研究描述了一种稳健有效的方法来生成抗动脉粥样硬化单核细胞,描述了靶向单核细胞重编程的新机制,并提供了一种基于提供重编程抗动脉粥样硬化单核细胞的精准疗法。
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来源期刊
Circulation research
Circulation research 医学-外周血管病
CiteScore
29.60
自引率
2.00%
发文量
535
审稿时长
3-6 weeks
期刊介绍: Circulation Research is a peer-reviewed journal that serves as a forum for the highest quality research in basic cardiovascular biology. The journal publishes studies that utilize state-of-the-art approaches to investigate mechanisms of human disease, as well as translational and clinical research that provide fundamental insights into the basis of disease and the mechanism of therapies. Circulation Research has a broad audience that includes clinical and academic cardiologists, basic cardiovascular scientists, physiologists, cellular and molecular biologists, and cardiovascular pharmacologists. The journal aims to advance the understanding of cardiovascular biology and disease by disseminating cutting-edge research to these diverse communities. In terms of indexing, Circulation Research is included in several prominent scientific databases, including BIOSIS, CAB Abstracts, Chemical Abstracts, Current Contents, EMBASE, and MEDLINE. This ensures that the journal's articles are easily discoverable and accessible to researchers in the field. Overall, Circulation Research is a reputable publication that attracts high-quality research and provides a platform for the dissemination of important findings in basic cardiovascular biology and its translational and clinical applications.
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