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 a...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.展开更多
Liver sinusoidal endothelial cells （LSECs） line the liver sinusoids and separate passenger leukocytes in the sinusoidal lumen from hepatocytes. LSECs further act as a platform for adhesion of various liver-resident ...Liver sinusoidal endothelial cells （LSECs） line the liver sinusoids and separate passenger leukocytes in the sinusoidal lumen from hepatocytes. LSECs further act as a platform for adhesion of various liver-resident immune cell populations such as Kupffer cells, innate lymphoid cells or liver dendritic cells. In addition to having an extraordinary scavenger function, LSECs possess potent immune functions, serving as sentinel cells to detect microbial infection through pattern recognition receptor activation and as antigen （cross）-presenting cells. LSECs cross-prime naive CD8 T cells, causing their rapid differentiation into memory T cells that relocate to secondary lymphoid tissues and provide protection when they re-encounter the antigen during microbial infection. Cross-presentation of viral antigens by LSECs derived from infected hepatocytes triggers local activation of effector CD8 T cells and thereby assures hepatic immune surveillance. The immune function of LSECs complements conventional immune-activating mechanisms to accommodate optimal immune surveillance against infectious microorganisms while preserving the integrity of the liver as a metabolic organ.展开更多
基金This work was supported by grants from the National Natural Science Foundation of China(31730041,31671523,and 81470416).
文摘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.
文摘Liver sinusoidal endothelial cells （LSECs） line the liver sinusoids and separate passenger leukocytes in the sinusoidal lumen from hepatocytes. LSECs further act as a platform for adhesion of various liver-resident immune cell populations such as Kupffer cells, innate lymphoid cells or liver dendritic cells. In addition to having an extraordinary scavenger function, LSECs possess potent immune functions, serving as sentinel cells to detect microbial infection through pattern recognition receptor activation and as antigen （cross）-presenting cells. LSECs cross-prime naive CD8 T cells, causing their rapid differentiation into memory T cells that relocate to secondary lymphoid tissues and provide protection when they re-encounter the antigen during microbial infection. Cross-presentation of viral antigens by LSECs derived from infected hepatocytes triggers local activation of effector CD8 T cells and thereby assures hepatic immune surveillance. The immune function of LSECs complements conventional immune-activating mechanisms to accommodate optimal immune surveillance against infectious microorganisms while preserving the integrity of the liver as a metabolic organ.
