CD47-Mediated Hedgehog/SMO/GLI1 Signaling Promotes Mesenchymal Stem Cell Immunomodulation in Mouse Liver Inflammation.
CD47-Mediated Hedgehog/SMO/GLI1 Signaling Promotes Mesenchymal Stem Cell Immunomodulation in Mouse Liver Inflammation.
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CD 47介导的Hedgehog/SMO/GLI 1信号通路促进小鼠肝脏炎症中的间充质干细胞免疫调节
DOI：
10.1002/hep.31831
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发表时间：
2021-09
期刊：
影响因子：
13.5
通讯作者：
Ke, Bibo
中科院分区：
文献类型：
--
作者：
Sheng, Mingwei;Lin, Yuanbang;Xu, Dongwei;Tian, Yizhu;Zhan, Yongqiang;Li, Changyong;Farmer, Douglas G.;Kupiec-Weglinski, Jerzy W.;Ke, Bibo
CD 47信号调节蛋白α（SIRPα）信号通路在免疫稳态和组织炎症反应中起重要作用。Hedgehog/SMO/Gli 1途径的激活调节细胞生长、分化和免疫功能。然而，在无菌性炎性肝损伤过程中，CD 47-SIRPα相互作用是否以及如何调节间充质干细胞（MSC）介导的免疫调节中的Hedgehog/SMO/Gli 1信号转导仍然是未知的。在缺血/再灌注（IR）诱导的无菌性炎症性肝损伤小鼠模型中，我们发现过继转移MSC增加了CD 47表达，改善了肝脏IRI。然而，MSC中CD 47的缺失加剧了IR诱导的肝损伤，血清ALT水平升高，巨噬细胞/中性粒细胞浸润和促炎介质增加。MSC处理增强了SIRPα、Hedgehog/SMO/Gli 1和Notch 1胞内结构域（NICD），而CD 47缺陷MSC处理降低了IR应激肝脏中这些基因的表达。此外，髓系SMO或Notch 1的破坏增加了IR触发的肝脏炎症，减少了Gli 1和NICD，但增强了MSC转移小鼠中的NEK 7和NLRP 3活化。采用MSC/巨噬细胞共培养体系，发现LPS刺激后MSC CD 47和巨噬细胞SIRPα表达增加。CD 47-SIRPα相互作用增加巨噬细胞Gli 1和NICD核转位，从而NICD与Gli 1相互作用并调节其靶基因Dvl 2，Dvl 2反过来抑制NEK 7/NLRP 3活性。CD 47-SIRPα信号激活Hedgehog/SMO/Gli 1通路，该通路通过Gli 1和NICD之间的直接相互作用控制NEK 7/NLRP 3活性。NICD是Gli 1的一种新型共激活因子，其调控的靶基因Dvl 2在MSC介导的免疫调节中对NLRP 3驱动的炎症反应的调节起着至关重要的作用。我们的研究结果为MSC介导的无菌性炎性肝损伤的免疫治疗提供了新的潜在治疗靶点。
The CD47-signal regulatory protein alpha (SIRPα) signaling pathway plays important roles in immune homeostasis and tissue inflammatory response. Activation of the Hedgehog/SMO/Gli1 pathway regulates cell growth, differentiation, and immune function. However, it remains unknown whether and how the CD47-SIRPα interaction may regulate Hedgehog/SMO/Gli1 signaling in mesenchymal stem cell (MSC)-mediated immune regulation during sterile inflammatory liver injury. In a mouse model of ischemia/reperfusion (IR)-induced sterile inflammatory liver injury, we found that adoptive transfer of MSCs increased CD47 expression and ameliorated liver IRI. However, deletion of CD47 in MSCs exacerbated IR-induced liver damage, with increased serum ALT levels, macrophage/neutrophil infiltration, and pro-inflammatory mediators. MSC treatment augmented SIRPα, Hedgehog/SMO/Gli1, and Notch1 intracellular domain (NICD), whereas CD47-deficient MSC treatment reduced these gene expressions in IR-stressed livers. Moreover, disruption of myeloid SMO or Notch1 increased IR-triggered liver inflammation with diminished Gli1 and NICD but enhanced NEK7 and NLRP3 activation in MSC-transferred mice. Using a MSC/macrophage co-culture system, we found that MSC CD47 and macrophage SIRPα expression were increased after LPS stimulation. The CD47-SIRPα interaction increased macrophage Gli1 and NICD nuclear translocation, whereby NICD interacted with Gli1 and regulated its target gene Dvl2, which in turn inhibited NEK7/NLRP3 activity. The CD47-SIRPα signaling activates the Hedgehog/SMO/Gli1 pathway, which controls NEK7/NLRP3 activity through a direct interaction between Gli1 and NICD. NICD is a novel coactivator of Gli1, and the target gene Dvl2 regulated by the NICD-Gli1 complex is crucial for the modulation of NLRP3-driven inflammatory response in MSC-mediated immune regulation. Our findings provide novel potential therapeutic targets in MSC-mediated immunotherapy of sterile inflammatory liver injury.
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影响因子：
25.7
作者：
Li, Changyong;Kong, Yaxian;Li, Liying
通讯作者：
Li, Liying
影响因子：
4
作者：
Gammons MV;Rutherford TJ;Steinhart Z;Angers S;Bienz M
通讯作者：
Bienz M
DOI：
10.1073/pnas.1616447113
发表时间：
2016-11-22
影响因子：
11.1
作者：
Lee, John J.;Rothenberg, Michael E.;Beachy, Philip A.
通讯作者：
Beachy, Philip A.
影响因子：
13.5
作者：
Köhler, C;Bell, AW;Michalopoulos, GK
通讯作者：
Michalopoulos, GK
影响因子：
4.3
作者：
Contreras RA;Figueroa FE;Djouad F;Luz-Crawford P
通讯作者：
Luz-Crawford P