Endothelial Shp2 deficiency controls alternative activation of macrophage preventing radiation-induced lung injury through notch signaling.
Endothelial Shp2 deficiency controls alternative activation of macrophage preventing radiation-induced lung injury through notch signaling.
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内皮Shp2缺陷控制巨噬细胞的替代激活，通过Notch信号传导预防辐射引起的肺损伤
DOI：
10.1016/j.isci.2022.103867
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发表时间：
2022-03-18
期刊：
影响因子：
5.8
通讯作者：
Zhang X
中科院分区：
文献类型：
--
作者：
Liu P;Li Y;Li M;Zhou H;Zhang H;Zhang Y;Xu J;Xu Y;Zhang J;Xia B;Cheng H;Ke Y;Zhang X
放射性肺损伤是胸部放射治疗常见的晚期副作用。白细胞渗入后的内皮功能障碍是这一过程的一个显著特征。在这里，我们建立了一种模拟临床的小鼠放射性肺损伤模型，发现肺损伤后内皮细胞中磷酸酶Shp2的活性升高。内皮特异性Shp2缺失的小鼠表现出胶原沉积减轻，并伴随着辐射诱导的内皮Jag1表达中断。此外，内皮来源的Jag1在体内外通过旁分泌Notch信号激活巨噬细胞的交替激活。一直以来，胸部照射显著激活了癌症患者外周血白细胞中的Notch通路。总之，我们的工作表明Shp2参与了辐射诱导的内皮功能障碍，并随后在辐射诱导的肺损伤过程中产生了炎性微环境。我们的研究结果表明Shp2是放射性肺损伤的潜在靶点，并为内皮细胞参与放射性肺损伤的病理过程提供了另一种途径。Shp2基因缺陷的内皮细胞中Shp2的缺失减轻放射性肺损伤Shp2基因缺陷的内皮细胞通过Notch信号抑制巨噬细胞活化
Radiation-induced lung injury is a common late side effect of thoracic radiotherapy. Endothelial dysfunction following leukocytes infiltration is a prominent feature in this process. Here, we established a clinical-mimicking mouse model of radiation-induced lung injury and found the activity of phosphatase Shp2 was elevated in endothelium after injury. Endothelium-specific Shp2 deletion mice showed relieved collagen deposition along with disrupted radiation-induced Jag1 expression in the endothelium. Furthermore, endothelium-derived Jag1 activated the alternative activation of macrophages in vitro and in vivo by paracrine Notch signaling. Consistently, the Notch pathway was significantly activated by chest irradiation in the peripheral blood leukocytes of patients with cancer. Collectively, our work demonstrates that Shp2 participates in the radiation-induced endothelial dysfunction and subsequently inflammatory microenvironment producing during radiation-induced lung injury. Our findings indicate Shp2 as a potential target for radiation-induced lung injury and provide another way for endothelium to participate in the pathological process of radiation-induced lung injury. Phosphatase activity of endothelial Shp2 is elevated by irradiation in vitro and in vivo Radiation-induced Jag1 is blocked in Shp2-deficient endothelium Loss of Shp2 in endothelium relieves radiation-induced pulmonary injury Shp2-deficient endothelium restrains macrophage activation via Notch signaling Biological sciences; Immunology; Molecular biology; Transcriptomics
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影响因子：
82.9
作者：
Dardaei L;Wang HQ;Singh M;Fordjour P;Shaw KX;Yoda S;Kerr G;Yu K;Liang J;Cao Y;Chen Y;Lawrence MS;Langenbucher A;Gainor JF;Friboulet L;Dagogo-Jack I;Myers DT;Labrot E;Ruddy D;Parks M;Lee D;DiCecca RH;Moody S;Hao H;Mohseni M;LaMarche M;Williams J;Hoffmaster K;Caponigro G;Shaw AT;Hata AN;Benes CH;Li F;Engelman JA
通讯作者：
Engelman JA
放疗后通过内皮到间质转变的肿瘤 - 脉管系统通过控制CD44V6（+）癌细胞和巨噬细胞极化。
影响因子：
16.6
作者：
Choi SH;Kim AR;Nam JK;Kim JM;Kim JY;Seo HR;Lee HJ;Cho J;Lee YJ
通讯作者：
Lee YJ
影响因子：
28.2
作者：
Fedele C;Ran H;Diskin B;Wei W;Jen J;Geer MJ;Araki K;Ozerdem U;Simeone DM;Miller G;Neel BG;Tang KH
通讯作者：
Tang KH
影响因子：
11.5
作者：
Choi, Seo-Hyun;Hong, Zhen-Yu;Lee, Yoon-Jin
通讯作者：
Lee, Yoon-Jin
影响因子：
3.1
作者：
Cheng Y;Yu M;Xu J;He M;Wang H;Kong H;Xie W
通讯作者：
Xie W