Inhibition of macrophage histone demethylase JMJD3 protects against abdominal aortic aneurysms.
Inhibition of macrophage histone demethylase JMJD3 protects against abdominal aortic aneurysms.
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DOI：
10.1084/jem.20201839
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发表时间：
2021-06-07
期刊：
影响因子：
--
通讯作者：
Gallagher KA
中科院分区：
文献类型：
--
作者：
Davis FM;Tsoi LC;Melvin WJ;denDekker A;Wasikowski R;Joshi AD;Wolf S;Obi AT;Billi AC;Xing X;Audu C;Moore BB;Kunkel SL;Daugherty A;Lu HS;Gudjonsson JE;Gallagher KA
腹主动脉瘤（AAA）是一种危及生命的疾病，其特征是巨噬细胞浸润导致病理性血管重塑。在此，我们证明组蛋白去甲基化酶JMJD 3是AAA发展过程中炎症的关键调节因子，细胞特异性抑制可减少AAA进展。腹主动脉瘤（AAA）是一种危及生命的疾病，目前缺乏有效的治疗方法来预防主动脉破裂。在AAA形成过程中，病理性血管重塑是由巨噬细胞浸润驱动的，调节巨噬细胞介导的炎症的机制仍不明确。最近的证据表明，表观遗传酶，JMJD 3，在建立巨噬细胞表型中起着关键作用。使用人AAA组织的单细胞RNA测序，我们鉴定了主动脉单核细胞/巨噬细胞中增加的JMJD 3，导致炎症免疫应答的上调。从机制上讲，我们报道干扰素-β通过JAK/STAT调节Jmjd 3表达，Jmjd 3诱导NF-κ B介导的浸润性主动脉巨噬细胞中的炎症基因转录。在弹性蛋白酶或血管紧张素II诱导的AAA模型中，通过骨髓特异性遗传耗竭（JMJD 3f/fLyz 2Cre+）或药理学抑制体内靶向抑制JMJD 3，可保留炎症基因启动子上的抑制性H3 K27 me 3，并显著减少AAA扩张和减弱巨噬细胞介导的炎症。总之，我们的研究结果表明，靶向JMJD 3的细胞特异性药物治疗可能是AAA扩张的有效干预。
Abdominal aortic aneurysms (AAAs) are a life-threatening disease characterized by macrophage infiltration contributing to pathological vascular remodeling. Herein, we demonstrate that the histone demethylase JMJD3 is a critical regulator of inflammation during AAA development and cell-specific inhibition reduces AAA progression. Abdominal aortic aneurysms (AAAs) are a life-threatening disease for which there is a lack of effective therapy preventing aortic rupture. During AAA formation, pathological vascular remodeling is driven by macrophage infiltration, and the mechanisms regulating macrophage-mediated inflammation remain undefined. Recent evidence suggests that an epigenetic enzyme, JMJD3, plays a critical role in establishing macrophage phenotype. Using single-cell RNA sequencing of human AAA tissues, we identified increased JMJD3 in aortic monocyte/macrophages resulting in up-regulation of an inflammatory immune response. Mechanistically, we report that interferon-β regulates Jmjd3 expression via JAK/STAT and that JMJD3 induces NF-κB–mediated inflammatory gene transcription in infiltrating aortic macrophages. In vivo targeted inhibition of JMJD3 with myeloid-specific genetic depletion (JMJD3f/fLyz2Cre+) or pharmacological inhibition in the elastase or angiotensin II–induced AAA model preserved the repressive H3K27me3 on inflammatory gene promoters and markedly reduced AAA expansion and attenuated macrophage-mediated inflammation. Together, our findings suggest that cell-specific pharmacologic therapy targeting JMJD3 may be an effective intervention for AAA expansion.
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DOI：
10.1161/atvbaha.112.300432
发表时间：
2013-02
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Johnston WF;Salmon M;Su G;Lu G;Stone ML;Zhao Y;Owens GK;Upchurch GR Jr;Ailawadi G
通讯作者：
Ailawadi G
影响因子：
4.3
作者：
Galán M;Varona S;Orriols M;Rodríguez JA;Aguiló S;Dilmé J;Camacho M;Martínez-González J;Rodriguez C
通讯作者：
Rodriguez C
DOI：
10.1161/atvbaha.118.312135
发表时间：
2019-04-01
影响因子：
8.7
作者：
Davis, Frank M.;Gallagher, Katherine A.
通讯作者：
Gallagher, Katherine A.
影响因子：
5.3
作者：
Huang, Aric;Young, Tayler L.;Werstuck, Geoff H.
通讯作者：
Werstuck, Geoff H.
影响因子：
46.9
作者：
Butler A;Hoffman P;Smibert P;Papalexi E;Satija R
通讯作者：
Satija R