Endothelial Notch activation promotes neutrophil transmigration via downregulating endomucin to aggravate hepatic ischemia/reperfusion injury
Endothelial Notch activation promotes neutrophil transmigration via downregulating endomucin to aggravate hepatic ischemia/reperfusion injury
复制标题
内皮Notch激活通过下调内粘蛋白促进中性粒细胞迁移加重肝缺血/再灌注损伤
DOI：
10.1007/s11427-019-1596-4
复制
发表时间：
2020-02
期刊：
影响因子：
--
通讯作者：
Han Hua
中科院分区：
文献类型：
--
作者：
Zhang Pei-Ran;Yue Kang-Yi;Liu Xin-Li;Yan Xian-Chun;Yang Zi-Yan;Duan Juan-Li;Xia Cong-Cong;Xu Xin-Yuan;Zhang Mei;Liang Liang;Wang Lin;Han Hua
炎症性白细胞浸润是由涉及趋化因子，选择素，地址素和其他粘附分子来源于内皮细胞（EC）的机制，但他们如何响应炎症线索和协调白细胞迁移仍然是难以捉摸的。在这项研究中，使用肝缺血/再灌注损伤（HIRI）作为模型，我们确定了内皮Notch激活快速和动态诱导肝窦内皮细胞（LSECs）在急性炎症。在EC特异性Notch激活（NICeCA）小鼠中，HIRI诱导加重肝损伤。一致地，内皮Notch激活增强HIRI中的中性粒细胞浸润和肿瘤坏死因子（TNF）-α表达。转录组分析和进一步的qRT-PCR以及免疫荧光表明，内粘蛋白（EMCN），白细胞粘附的负调控因子，在来自NICeCA小鼠的LSEC中下调。野生型小鼠HIRI和缺氧/复氧损伤的体外培养EC中EMCN表达下调。Notch激活内皮细胞导致中性粒细胞粘附和跨内皮细胞迁移增加，EMCN过表达可消除这一作用。在经典Notch信号的整合转录因子RBPj缺乏的小鼠中，尽管巨大的窦畸形加重HIRI，但EMCN的表达上调;体外Notch阻断剂也上调EMCN并抑制中性粒细胞的跨内皮迁移。通过阻断LFA-1，Notch激活增强的HIRI受到损害，LFA-1通过与EMCN相关介导白细胞粘附。因此，内皮Notch信号转导通过EMCN控制中性粒细胞迁移，从而调节HIRI中的急性炎症。
Inflammatory leukocytes infiltration is orchestrated by mechanisms involving chemokines, selectins, addressins and other adhesion molecules derived from endothelial cells (ECs), but how they respond to inflammatory cues and coordinate leukocyte transmigration remain elusive. In this study, using hepatic ischemia/reperfusion injury (HIRI) as a model, we identified that endothelial Notch activation was rapidly and dynamically induced in liver sinusoidal endothelial cells (LSECs) in acute inflammation. In mice with EC-specific Notch activation (NICeCA), HIRI induced exacerbated liver damage. Consistently, endothelial Notch activation enhanced neutrophil infiltration and tumor necrosis factor (TNF)-α expression in HIRI. Transcriptome analysis and further qRT-PCR as well as immunofluorescence indicated that endomucin (EMCN), a negative regulator of leukocyte adhesion, was downregulated in LSECs from NICeCAmice. EMCN was downregulated during HIRI in wild-type mice andin vitrocultured ECs insulted by hypoxia/re-oxygenation injury. Notch activation in ECs led to increased neutrophil adhesion and transendothelial migration, which was abrogated by EMCN overexpressionin vitro. In mice deficient of RBPj, the integrative transcription factor of canonical Notch signaling, although overwhelming sinusoidal malformation aggravated HIRI, the expression of EMCN was upregulated; and pharmaceutical Notch blockadein vitroalso upregulated EMCN and inhibited transendothelial migration of neutrophils. The Notch activation-exaggerated HIRI was compromised by blocking LFA-1, which mediated leukocyte adherence by associating with EMCN. Therefore, endothelial Notch signaling controls neutrophil transmigration via EMCN to modulate acute inflammation in HIRI.
登录
查看更多内容
影响因子：
4.4
作者：
Bharadwaj, Arpita S.;Schewitz-Bowers, Lauren P.;Smith, Justine R.
通讯作者：
Smith, Justine R.
内皮缺口信号传导对于预防小鼠肝血管畸形至关重要。
DOI：
10.1002/hep.28713
发表时间：
2016-10
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Cuervo H;Nielsen CM;Simonetto DA;Ferrell L;Shah VH;Wang RA
通讯作者：
Wang RA
影响因子：
21.1
作者：
Shang Y;Smith S;Hu X
通讯作者：
Hu X
经典Notch通路通过JAK2/STAT3信号传导抑制活性氧的产生，保护小鼠肝细胞免受缺血/再灌注损伤
影响因子：
13.5
作者：
Yu, Heng-Chao;Qin, Hong-Yan;Han, Hua
通讯作者：
Han, Hua
影响因子：
32.4
作者：
Tanigaki, K;Tsuji, M;Honjo, T
通讯作者：
Honjo, T