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AIM2炎症小体加剧动脉粥样硬化风险
2021-03-18 16:12

美国哥伦比亚大学欧文医学中心Alan R. Tall、Nan Wang等研究组合作取得最新进展。他们表明AIM2炎症小体加剧了克隆型造血干细胞的动脉粥样硬化。这一研究成果发表在2021年3月17日出版的国际学术期刊《自然》杂志上。

他们显示了在巨噬细胞中选择性表达JAK2V617F(JAK2VF)的小鼠和模拟克隆性造血功能的嵌合小鼠的动脉粥样硬化病变中,巨噬细胞增殖增加和坏死核心明显形成。敲除必需的炎症小体半胱氨酸天冬氨酸蛋白酶1和11,或敲除细胞焦亡执行者gasdermin D,可以逆转这些不利变化。 Jak2VF病变显示AIM2表达增加,氧化性DNA损伤和DNA复制压力,而Aim2缺乏降低了动脉粥样硬化。

对Jak2VF病变的单细胞RNA测序分析揭示了富含炎症性骨髓细胞的景观,该炎症细胞被Gsdmd的缺失所抑制。炎性小体产物白介素-1β的抑制作用减少了巨噬细胞的增殖和坏死的形成,同时增加了纤维帽的厚度,表明它可以稳定斑块。他们的发现表明,Jak2VF巨噬细胞中增殖和糖酵解代谢的增加会导致DNA复制压力和AIM2炎症小体的激活,从而加剧动脉粥样硬化。根据克隆性造血作用的状态精确应用针对白介素-1β或特定炎症小体的疗法,可大大降低心血管疾病的风险。

据了解,克隆性造血在老年人中非常普遍,源于赋予造血细胞增殖优势的体细胞突变。克隆性造血增加了心肌梗塞和中风的风险,而不受传统风险因素的影响。在引起克隆性造血的常见遗传变异中,JAK2VF突变增加了JAK-STAT信号传导,发生在年幼时,并赋予了最强的早发冠心病风险。

附:英文原文

Title: The AIM2 inflammasome exacerbates atherosclerosis in clonal haematopoiesis

Author: Trevor P. Fidler, Chenyi Xue, Mustafa Yalcinkaya, Brian Hardaway, Sandra Abramowicz, Tong Xiao, Wenli Liu, David G. Thomas, Mohammad Ali Hajebrahimi, Joachim Pircher, Carlos Silvestre-Roig, Andriana G. Kotini, Larry L. Luchsinger, Ying Wei, Marit Westerterp, Hans-Willem Snoeck, Eirini P. Papapetrou, Christian Schulz, Steffen Massberg, Oliver Soehnlein, Benjamin Ebert, Ross L. Levine, Muredach P. Reilly, Peter Libby, Nan Wang, Alan R. Tall

Issue&Volume: 2021-03-17

Abstract: Clonal haematopoiesis, which is highly prevalent in older individuals, arises from somatic mutations that endow a proliferative advantage to haematopoietic cells. Clonal haematopoiesis increases the risk of myocardial infarction and stroke independently of traditional risk factors1. Among the common genetic variants that give rise to clonal haematopoiesis, the JAK2V617F (JAK2VF) mutation, which increases JAK–STAT signalling, occurs at a younger age and imparts the strongest risk of premature coronary heart disease1,2. Here we show increased proliferation of macrophages and prominent formation of necrotic cores in atherosclerotic lesions in mice that express Jak2VF selectively in macrophages, and in chimeric mice that model clonal haematopoiesis. Deletion of the essential inflammasome components caspase 1 and 11, or of the pyroptosis executioner gasdermin D, reversed these adverse changes. Jak2VF lesions showed increased expression of AIM2, oxidative DNA damage and DNA replication stress, and Aim2 deficiency reduced atherosclerosis. Single-cell RNA sequencing analysis of Jak2VF lesions revealed a landscape that was enriched for inflammatory myeloid cells, which were suppressed by deletion of Gsdmd. Inhibition of the inflammasome product interleukin-1β reduced macrophage proliferation and necrotic formation while increasing the thickness of fibrous caps, indicating that it stabilized plaques. Our findings suggest that increased proliferation and glycolytic metabolism in Jak2VF macrophages lead to DNA replication stress and activation of the AIM2 inflammasome, thereby aggravating atherosclerosis. Precise application of therapies that target interleukin-1β or specific inflammasomes according to clonal haematopoiesis status could substantially reduce cardiovascular risk.

DOI: 10.1038/s41586-021-03341-5

Source: https://www.nature.com/articles/s41586-021-03341-5

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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