Radiation-Induced Macrophage Senescence Impairs Resolution Programs and Drives Cardiovascular Inflammation.
Radiation-Induced Macrophage Senescence Impairs Resolution Programs and Drives Cardiovascular Inflammation.
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DOI：
10.4049/jimmunol.2100284
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发表时间：
2021-10-01
期刊：
影响因子：
--
通讯作者：
Fredman G
中科院分区：
文献类型：
--
作者：
Sadhu S;Decker C;Sansbury BE;Marinello M;Seyfried A;Howard J;Mori M;Hosseini Z;Arunachalam T;Finn AV;Lamar JM;Jourd'heuil D;Guo L;MacNamara KC;Spite M;Fredman G
辐射与组织损伤和动脉粥样硬化风险增加有关，但目前还没有治疗方法，对辐射如何影响组织修复机制的机械理解也非常有限。我们发现，辐射显著延迟了与体内泡腾作用减少相关的时间分辨程序。分解蛋白D1(RvD1)是一种已知的前分解配体，可促进亚致死剂量照射小鼠的快速分解和恢复泡腾作用。照射后的巨噬细胞在体外表现出多个衰老特征，包括p16INK4A和p21的表达增加，SA-β-GAL、COX-2、几种促炎细胞因子/趋化因子的水平升高，以及氧化应激(OS)，当被转移到小鼠体内时，炎症加剧。从机制上讲，衰老巨噬细胞中OS的升高导致其进行有效的吞噬作用的能力受损，而RvD1治疗减少了OS并改善了吞噬作用。亚致死剂量照射的−/−小鼠与非照射对照组相比，斑块坏死增加，p16INK4A细胞增多，皮损胶原减少，皮损胶原增加，坏死明显减轻。在p16-3MR小鼠的晚期动脉粥样硬化期间，去除p16INK4A造血细胞可以减少斑块坏死并增加关键斑块内分解介质的产生。我们的结果表明，亚致死剂量的辐射导致巨噬细胞衰老和吞噬缺陷，提示RvD1可能是限制辐射诱导的组织损伤的一种新的治疗策略。
Radiation is associated with tissue damage and increased risk of atherosclerosis but there are currently no treatments and a very limited mechanistic understanding of how radiation impacts tissue repair mechanisms. We uncovered that radiation significantly delayed temporal resolution programs that were associated with decreased efferocytosis in vivo. Resolvin D1 (RvD1), a known pro-resolving ligand, promoted swift resolution and restored efferocytosis in sublethally irradiated mice. Irradiated macrophages exhibited several features of senescence, including increased expression of p16INK4A and p21, heightened levels of SA- β-gal, COX-2, several pro-inflammatory cytokines/chemokines, and oxidative stress (OS) in vitro, and when transferred to mice exacerbated inflammation in vivo. Mechanistically, heightened OS in senescent macrophages led to impairment in their ability to carry out efficient efferocytosis and treatment with RvD1 reduced OS and improved efferocytosis. Sublethally irradiated Ldlr−/− mice exhibited increased plaque necrosis, p16INK4A cells and decreased lesional collagen compared with non-irradiated controls and treatment with RvD1 significantly reduced necrosis and increased lesional collagen. Removal of p16INK4A hematopoietic cells during advanced atherosclerosis with p16-3MR mice reduced plaque necrosis and increased production of key intraplaque resolving mediators. Our results demonstrate that sublethal radiation drives macrophage senescence and efferocytosis defects and suggest that RvD1 may be a new therapeutic strategy to limit radiation-induced tissue damage.
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影响因子：
158.5
作者：
Darby, Sarah C.;Ewertz, Marianne;Hall, Per
通讯作者：
Hall, Per
影响因子：
64.5
作者：
Moore KJ;Tabas I
通讯作者：
Tabas I
DOI：
10.1007/978-1-4939-7592-1_4
发表时间：
2018-01-01
期刊：
CLINICAL METABOLOMICS: METHODS AND PROTOCOLS
影响因子：
--
作者：
Dalli, Jesmond;Colas, Romain A.;Serhan, Charles N.
通讯作者：
Serhan, Charles N.
影响因子：
16.6
作者：
Fredman, Gabrielle;Hellmann, Jason;Proto, Jonathan D.;Kuriakose, George;Colas, Romain A.;Dorweiler, Bernhard;Connolly, E. Sander;Solomon, Robert;Jones, David M.;Heyer, Eric J.;Spite, Matthew;Tabas, Ira
通讯作者：
Tabas, Ira
影响因子：
21.3
作者：
Rodier, Francis;Coppe, Jean-Philippe;Patil, Christopher K.;Hoeijmakers, Wieteke A. M.;Munoz, Denise P.;Raza, Saba R.;Freund, Adam;Campeau, Eric;Davalos, Albert R.;Campisi, Judith
通讯作者：
Campisi, Judith