Notch-activated mesenchymal stromal/stem cells enhance the protective effect against acetaminophen-induced acute liver injury by activating AMPK/SIRT1 pathway.
Notch-activated mesenchymal stromal/stem cells enhance the protective effect against acetaminophen-induced acute liver injury by activating AMPK/SIRT1 pathway.
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Notch激活的间充质基质/干细胞通过激活AMPK/SIRT1通路增强对乙酰氨基酚诱导的急性肝损伤的保护作用
DOI：
10.1186/s13287-022-02999-6
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发表时间：
2022-07-16
影响因子：
7.5
通讯作者：
中科院分区：
文献类型：
--
作者：
Notch信号在天然免疫调节中起重要作用。然而，Notch在肝脏炎症反应中间充质基质/干细胞（MSC）介导的免疫调节中的作用知之甚少。通过用Notch配体重组人锯齿蛋白1（JAG 1）包被的组织培养板进行人脐带来源的MSC中的Notch活化。对乙酰氨基酚（APAP）诱导小鼠急性肝损伤后，静脉注射Notch激活的MSCs。收集肝组织并进行组织学和免疫组织化学分析。MSC给药减少APAP诱导的肝细胞损伤，表现为血清ALT水平降低、肝内巨噬细胞/中性粒细胞浸润、肝细胞凋亡和促炎介质。Notch通过其配体JAG 1激活MSC的抗炎活性和治疗效果大大增强。然而，即使在JAG 1预处理的存在下，MSC中Notch 2的破坏也显著降低了MSC对APAP诱导的急性肝损伤的保护作用。引人注目的是，Notch激活的MSC促进AMP激活蛋白激酶（AMPKα）磷酸化，增加sirtuins 1（SIRT 1）脱乙酰酶表达，但下调剪接的X-box-binding蛋白1（XBP 1 s）表达，从而减少NLR家族含pyrin结构域3（NLRP 3）炎性小体激活。此外，巨噬细胞中SIRT 1破坏或XBP 1 s过表达加剧了APAP触发的肝脏炎症，并增强了MSC给药小鼠中NLRP 3/caspase-1的活性。机制研究进一步表明，JAG 1预处理的MSC激活Notch 2/COX 2/PGE 2信号传导，这反过来诱导巨噬细胞AMPK/SIRT 1激活，导致XBP 1 s脱乙酰化和NLRP 3活性抑制。Notch 2的激活是MSC降低小鼠中APAP诱导的肝损伤严重程度的能力所必需的。我们的研究结果为阐明MSC通过激活Notch 2/COX 2/AMPK/SIRT 1通路介导的免疫调节提供了新的分子视角，从而为肝脏炎症性疾病的治疗提供了新的策略。在线版本包含补充材料，可通过10.1186/s13287-022-02999-6获得。
Notch signaling plays important roles in regulating innate immunity. However, little is known about the role of Notch in mesenchymal stromal/stem cell (MSC)-mediated immunomodulation during liver inflammatory response. Notch activation in human umbilical cord-derived MSCs was performed by a tissue culture plate coated with Notch ligand, recombinant human Jagged1 (JAG1). Mice were given intravenous injection of Notch-activated MSCs after acetaminophen (APAP)-induced acute liver injury. Liver tissues were collected and analyzed by histology and immunohistochemistry. MSC administration reduced APAP-induced hepatocellular damage, as manifested by decreased serum ALT levels, intrahepatic macrophage/neutrophil infiltration, hepatocellular apoptosis and proinflammatory mediators. The anti-inflammatory activity and therapeutic effects of MSCs were greatly enhanced by Notch activation via its ligand JAG1. However, Notch2 disruption in MSCs markedly diminished the protective effect of MSCs against APAP-induced acute liver injury, even in the presence of JAG1 pretreatment. Strikingly, Notch-activated MSCs promoted AMP-activated protein kinase (AMPKα) phosphorylation, increased the sirtuins 1 (SIRT1) deacetylase expression, but downregulated spliced X-box-binding protein 1 (XBP1s) expression and consequently reduced NLR family pyrin domain-containing 3 (NLRP3) inflammasome activation. Furthermore, SIRT1 disruption or XBP1s overexpression in macrophages exacerbated APAP-triggered liver inflammation and augmented NLRP3/caspase-1 activity in MSC-administrated mice. Mechanistic studies further demonstrated that JAG1-pretreated MSCs activated Notch2/COX2/PGE2 signaling, which in turn induced macrophage AMPK/SIRT1 activation, leading to XBP1s deacetylation and inhibition of NLRP3 activity. Activation of Notch2 is required for the ability of MSCs to reduce the severity of APAP-induced liver damage in mice. Our findings underscore a novel molecular insights into MSCs-mediated immunomodulation by activating Notch2/COX2/AMPK/SIRT1 pathway and thus provide a new strategy for the treatment of liver inflammatory diseases. The online version contains supplementary material available at 10.1186/s13287-022-02999-6.
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影响因子：
5.2
作者：
Bartosh, Thomas J.;Yloestalo, Joni H.;Bazhanov, Nikolay;Kuhlman, Jessica;Prockop, Darwin J.
通讯作者：
Prockop, Darwin J.
影响因子：
12.4
作者：
Li C;Sheng M;Lin Y;Xu D;Tian Y;Zhan Y;Jiang L;Coito AJ;Busuttil RW;Farmer DG;Kupiec-Weglinski JW;Ke B
通讯作者：
Ke B
影响因子：
13.5
作者：
Lebeaupin, Cynthia;Vallee, Deborah;Bailly-Maitre, Beatrice
通讯作者：
Bailly-Maitre, Beatrice
胆汁酸通过抑制 NLRP3 炎症小体控制炎症和代谢紊乱
影响因子：
32.4
作者：
Guo, Chuansheng;Xie, Shujun;Wang, Di
通讯作者：
Wang, Di
影响因子：
4.4
作者：
Biagioli, Michele;Carino, Adriana;Fiorucci, Stefano
通讯作者：
Fiorucci, Stefano