Endothelial Notch activation promotes neutrophil transmigration via downregulating endomucin to aggravate hepatic ischemia/reperfusion injury

查看全文 作　　者：Peiran [1,2]Zhang;Kangyi [1,2]Yue;Xinli [3]Liu;Xianchun [1,2]Yan;Ziyan [1,2]Yang;Juanli [3]Duan;Congcong [3]Xia;Xinyuan [1,2]Xu;Mei [1,2]Zhang;Liang [1,2]Liang;Lin [3]Wang;Hua [1,2]Han

机构地区：[1]State Key Laboratory of Cancer Biology,Fourth Military Medical University,Xi’an 710032,China;[2]Department of Biochemistry and Molecular Biology,Fourth Military Medical University,Xi’an 710032,China;[3]Department of Hepatobiliary Surgery,Xijing Hospital,Fourth Military Medical University,Xi’an 710032,China

出　　处：《Science China(Life Sciences)》索引2020年第63卷第3期,共13页

基　　金：This work was supported by grants from the National Natural Science Foundation of China(31730041,31671523,and 81470416). 摘　　要：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)-αexpression 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 NICeCA mice.EMCN was downregulated during HIRI in wild-type mice and in vitro cultured ECs insulted by hypoxia/re-oxygenation injury.Notch activation in ECs led to increased neutrophil adhesion and transendothelial migration,which was abrogated by EMCN overexpression in 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 blockade in vitro also 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. 关键词：LEUKOCYTE transendothelial migration HEPATIC ISCHEMIA/REPERFUSION injury(HIRI) liver sinusoidal ENDOTHELIAL cells(LSECs) Notch endomucin(EMCN)

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Endothelial Notch activation promotes neutrophil transmigration via downregulating endomucin to aggravate hepatic ischemia/reperfusion injury

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