The IRG1-itaconate axis protects from cholesterol-induced inflammation and atherosclerosis.
The IRG1-itaconate axis protects from cholesterol-induced inflammation and atherosclerosis.
复制标题
IRG1-衣康酸轴可防止胆固醇引起的炎症和动脉粥样硬化。
DOI：
10.1073/pnas.2400675121
复制
发表时间：
2024
影响因子：
11.1
通讯作者：
Schlegel,PMarti
中科院分区：
文献类型：
--
作者：
Cyr,Yannick;Bozal,FazliK;BarciaDurán,JoséGabriel;Newman,AlexandraAC;Amadori,Letizia;Smyrnis,Panagiotis;Gourvest,Morgane;Das,Dayasagar;Gildea,Michael;Kaur,Ravneet;Zhang,Tracy;Wang,KristinM;VonItter,Richard;Schlegel,PMarti
动脉粥样硬化是由于未能解决血管系统内的脂质驱动的炎症，从而导致斑块形成。需要逆转动脉粥样硬化炎症的治疗方法来解决全球心血管疾病（CVD）负担的增加。最近，代谢物因其免疫调节特性而受到关注，包括衣康酸，其通过酶免疫应答基因1（IRG 1/ACOD 1）从三羧酸中间体顺乌头酸产生。在这里，我们测试了IRG 1-衣康酸轴对人类动脉粥样硬化的治疗潜力。使用单细胞RNA测序（scRNA-seq），我们发现IRG 1在人类冠状动脉粥样硬化病变中的表达高于患者匹配的健康血管，在动脉粥样硬化小鼠模型中，IRG 1主要由斑块单核细胞、巨噬细胞和中性粒细胞表达。小鼠整体或造血Irg 1缺乏增加动脉粥样硬化负荷、斑块巨噬细胞和脂质含量以及促动脉粥样硬化细胞因子白细胞介素（IL）-1β的表达。从机制上讲，Irg 1的缺乏增加了巨噬细胞的脂质蓄积，并通过增加中性粒细胞胞外陷阱（NET）形成和NET引发巨噬细胞中的NLRP 3炎性小体加速炎症，导致IL-1β释放增加。相反，使用衣康酸4-辛酯（4-OI）补充Irg 1-衣康酸轴有益地重塑了小鼠中的晚期斑块并降低了病变IL-1β水平。为了研究4-OI在人体中的作用，我们利用了一种用于CVD药物发现的离体系统免疫学方法。使用来自CVD患者的血浆处理的外周血单核细胞的CyTOF和scRNA-seq，我们表明4-OI减弱促炎性磷酸信号传导并介导巨噬细胞群体的抗炎性重新布线。我们的数据突出了追求IRG 1-衣康酸轴补充作为人类动脉粥样硬化治疗方法的相关性。
Atherosclerosis is fueled by a failure to resolve lipid-driven inflammation within the vasculature that drives plaque formation. Therapeutic approaches to reverse atherosclerotic inflammation are needed to address the rising global burden of cardiovascular disease (CVD). Recently, metabolites have gained attention for their immunomodulatory properties, including itaconate, which is generated from the tricarboxylic acid-intermediate cis-aconitate by the enzyme Immune Responsive Gene 1 (IRG1/ACOD1). Here, we tested the therapeutic potential of the IRG1–itaconate axis for human atherosclerosis. Using single-cell RNA sequencing (scRNA-seq), we found thatIRG1is up-regulated in human coronary atherosclerotic lesions compared to patient-matched healthy vasculature, and in mouse models of atherosclerosis, where it is primarily expressed by plaque monocytes, macrophages, and neutrophils. Global or hematopoieticIrg1-deficiency in mice increases atherosclerosis burden, plaque macrophage and lipid content, and expression of the proatherosclerotic cytokine interleukin (IL)-1β. Mechanistically, absence ofIrg1increased macrophage lipid accumulation, and accelerated inflammation via increased neutrophil extracellular trap (NET) formation and NET-priming of the NLRP3-inflammasome in macrophages, resulting in increased IL-1β release. Conversely, supplementation of theIrg1–itaconate axis using 4-octyl itaconate (4-OI) beneficially remodeled advanced plaques and reduced lesional IL-1β levels in mice. To investigate the effects of 4-OI in humans, we leveraged an ex vivo systems-immunology approach for CVD drug discovery. Using CyTOF and scRNA-seq of peripheral blood mononuclear cells treated with plasma from CVD patients, we showed that 4-OI attenuates proinflammatory phospho-signaling and mediates anti-inflammatory rewiring of macrophage populations. Our data highlight the relevance of pursuing IRG1–itaconate axis supplementation as a therapeutic approach for atherosclerosis in humans.
登录
查看更多内容
亚利桑那州阿帕奇县卢卡丘凯山脉的铀矿开采，克尔麦吉石油工业公司
DOI：
--
发表时间：
1961
期刊：
影响因子：
--
作者：
W. L. Dare
通讯作者：
W. L. Dare
遭受原子弹袭击的父母的孩子：人类基因双倍辐射剂量的估计。
影响因子：
9.8
作者：
James V. Neel;W. Schull;A. A. Awa;Chiyoko Satoh;Hiroo Kato;Masanori Otake;Yasuhiko Yoshimoto
通讯作者：
Yasuhiko Yoshimoto
DOI：
--
发表时间：
1990
期刊：
影响因子：
--
作者：
H. Griffiths
通讯作者：
H. Griffiths
电离辐射遗传效应的最新进展。
DOI：
--
发表时间：
1991
期刊：
Journal of the American Medical Association (JAMA)
影响因子：
--
作者：
J. Neel
通讯作者：
J. Neel
血液和骨骼中 210Pb-210Po 的水平可作为吸入氡子体产品暴露程度的衡量标准。
影响因子：
2.2
作者：
Blanchard Rl;Archer Ve;G. Saccomanno
通讯作者：
G. Saccomanno