In vivo silencing of the transcription factor IRF5 reprograms the macrophage phenotype and improves infarct healing.
In vivo silencing of the transcription factor IRF5 reprograms the macrophage phenotype and improves infarct healing.
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DOI：
10.1016/j.jacc.2013.11.023
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发表时间：
2014-04-22
影响因子：
24
通讯作者：
Nahrendorf, Matthias
中科院分区：
文献类型：
--
作者：
Courties, Gabriel;Heidt, Timo;Sebas, Matthew;Iwamoto, Yoshiko;Jeon, Derrick;Truelove, Jessica;Tricot, Benoit;Wojtkiewicz, Greg;Dutta, Partha;Sager, Hendrik B.;Borodovsky, Anna;Novobrantseva, Tatiana;Klebanov, Boris;Fitzgerald, Kevin;Anderson, Daniel G.;Libby, Peter;Swirski, Filip K.;Weissleder, Ralph;Nahrendorf, Matthias
该研究的目的是测试心脏巨噬细胞中转录因子干扰素调节因子5 （IRF5）的沉默是否能改善梗死愈合并减轻心肌梗死后的重塑。在伤口愈合中，M1和M2巨噬细胞表型转化支持炎症和组织修复的解决。炎性M1巨噬细胞的持续存在可能破坏愈合并损害器官功能。转录因子IRF5促进与M1巨噬细胞相关的基因。在这里，我们使用纳米颗粒递送的siRNA来沉默小鼠心肌梗死（MI）和手术诱导皮肤伤口中巨噬细胞中的转录因子IRF5。梗死巨噬细胞在早期炎症伤口愈合阶段（冠状动脉结扎后第4天）表达高水平的IRF5，而转录因子的表达在炎症消退期间（第8天）下降。在体外筛选后，我们发现了一个siRNA序列，当纳米颗粒递送到伤口巨噬细胞时，可以有效抑制体内IRF5的表达。通过蛋白酶靶向FMT-CT成像和心脏MRI检测，IRF5表达降低（调节巨噬细胞极化的因子），减少炎症M1巨噬细胞标志物，支持炎症的消退，加速皮肤和梗死愈合，减轻冠状动脉结痂后心肌梗死心力衰竭的发展（p<0.05）。这项工作确定了一种新的治疗途径，通过巨噬细胞表型操作来增强愈合梗死炎症的解决。这种治疗理念可用于减轻心肌梗死后重构和心力衰竭。
The aim of the study was to test wether silencing of the transcription factor Interferon Regulatory Factor 5 (IRF5) in cardiac macrophages improves infarct healing and attenuates post-MI remodeling. In healing wounds, M1➛M2 macrophage phenotype transition supports resolution of inflammation and tissue repair. Persistence of inflammatory M1 macrophages may derail healing and compromise organ functions. The transcription factor IRF5 promotes genes associated with M1 macrophages. Here we used nanoparticle-delivered siRNA to silence the transcription factor IRF5 in macrophages residing in myocardial infarcts (MI) and in surgically induced skin wounds in mice. Infarct macrophages expressed high levels of IRF5 during the early inflammatory wound healing stages (day 4 after coronary ligation) whereas expression of the transcription factor decreased during the resolution of inflammation (day 8). Following in vitro screening, we identified an siRNA sequence that, when delivered by nanoparticles to wound macrophages, efficiently suppressed expression of IRF5 in vivo. Reduction of IRF5 expression, a factor that regulates macrophage polarization, reduced inflammatory M1 macrophage markers, supported resolution of inflammation, accelerated cutaneous and infarct healing and attenuated development of post-MI heart failure after coronary ligation as measured by protease targeted FMT-CT imaging and cardiac MRI (p<0.05 respectively). This work identifies a new therapeutic avenue to augment resolution of inflammation in healing infarcts by macrophage phenotype manipulation. This therapeutic concept may be used to attenuate post-MI remodeling and heart failure.
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DOI：
10.1038/mt.2011.263
发表时间：
2012-03
期刊：
Molecular therapy : the journal of the American Society of Gene Therapy
影响因子：
--
作者：
通讯作者：
--
影响因子：
64.5
作者：
Moore KJ;Tabas I
通讯作者：
Tabas I
DOI：
10.2353/ajpath.2010.090759
发表时间：
2010-05
期刊：
The American journal of pathology
影响因子：
--
作者：
Dobaczewski M;Xia Y;Bujak M;Gonzalez-Quesada C;Frangogiannis NG
通讯作者：
Frangogiannis NG
影响因子：
56.9
作者：
Peer, Dan;Park, Eun Jeong;Shimaoka, Motomu
通讯作者：
Shimaoka, Motomu
影响因子：
37.8
作者：
Nahrendorf M;Pittet MJ;Swirski FK
通讯作者：
Swirski FK