Kinsenoside attenuates liver fibro-inflammation by suppressing dendritic cells via the PI3K-AKT-FoxO1 pathway.
Kinsenoside attenuates liver fibro-inflammation by suppressing dendritic cells via the PI3K-AKT-FoxO1 pathway.
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Kinsenoside 通过 PI3K-AKT-FoxO1 途径抑制树突状细胞，从而减轻肝纤维炎症
DOI：
10.1016/j.phrs.2022.106092
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发表时间：
2022-03
影响因子：
9.3
通讯作者：
Zhang Y
中科院分区：
文献类型：
--
作者：
Xiang M;Liu T;Tian C;Ma K;Gou J;Huang R;Li S;Li Q;Xu C;Li L;Lee CH;Zhang Y
Kinsenoside（KD）具有抗炎和免疫抑制作用。树突状细胞（DC）是肝纤维化（LF）病理炎症环境的重要调节者。在此，我们探讨了KD是否以及如何通过DC调节抑制LF的发展，并验证了参与该过程的途径。根据我们的分析，KD和过继转移KD条件的DC显着减少肝组织病理学损伤，促炎细胞因子的释放和细胞外基质沉积在CCl 4诱导的LF小鼠。值得注意的是，KD抑制了LF驱动的CD 86、MHC-II和CCR 7水平的升高，同时特异性上调了DC上的PD-L1表达，这阻断了CD 8 +T细胞活化。KD可降低DC的糖酵解，维持DC的不成熟状态，并伴有DC中IL-12的减少。KD抑制DC的功能，可使DC与HSC之间的通讯受到干扰，肝脏α-SMA和Col-I的表达或分泌减少。在机制上，KD抑制由LF或PI 3 K激动剂驱动的PI 3 K-AKT的磷酸化，随后增强FoxO 1的核转运并上调FoxO 1与DC中PD-L1启动子的相互作用。PI 3 K抑制剂或si-IL-12作用于DC可减轻LF、HSC的活化，减弱KD的作用。总之，KD抑制DC成熟，通过PI 3 K-AKT-FoxO 1促进PD-L1表达并减少IL-12分泌，从而阻断CD 8 +T细胞和HSC的活化，从而减轻LF中的肝损伤和纤维化炎症。
Kinsenoside (KD) exhibits anti-inflammatory and immunosuppressive effects. Dendritic cells (DCs) are critical regulators of the pathologic inflammatory milieu in liver fibrosis (LF). Herein, we explored whether and how KD repressed development of LF via DC regulation and verified the pathway involved in the process. Given our analysis, both KD and adoptive transfer of KD-conditioned DCs conspicuously reduced hepatic histopathological damage, proinflammatory cytokine release and extracellular matrix deposition in CCl4-induced LF mice. Of note, KD restrained the LF-driven rise in CD86, MHC-II, and CCR7 levels and, simultaneously, upregulated PD-L1 expression on DCs specifically, which blocked CD8+T cell activation. Additionally, KD reduced DC glycolysis, maintained DCs immature, accompanied by IL-12 decrease in DCs. Inhibiting DC function by KD disturbed the communication of DCs and HSCs with the expression or secretion of α-SMA and Col-I declined in the liver. Mechanistically, KD suppressed the phosphorylation of PI3K-AKT driven by LF or PI3K agonist, followed by enhanced nuclear transport of FoxO1 and upregulated interaction of FoxO1 with the PD-L1 promoter in DCs. PI3K inhibitor or si-IL-12 acting on DC could relieve LF, HSC activation and diminish the effect of KD. In conclusion, KD suppressed DC maturation with promoted PD-L1 expression via PI3K-AKT-FoxO1 and decreased IL-12 secretion, which blocked activation of CD8+T cells and HSCs, thereby alleviating liver injury and fibro-inflammation in LF.
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影响因子：
7.3
作者：
Fontes-Cal TCM;Mattos RT;Medeiros NI;Pinto BF;Belchior-Bezerra M;Roque-Souza B;Dutra WO;Ferrari TCA;Vidigal PVT;Faria LC;Couto CA;Gomes JAS
通讯作者：
Gomes JAS
影响因子：
4.4
作者：
Hill, JA;Ichim, TE;Min, WP
通讯作者：
Min, WP
影响因子：
64.8
作者：
Dudek, Michael;Pfister, Dominik;Knolle, Percy A.
通讯作者：
Knolle, Percy A.
影响因子：
12.4
作者：
Gupta, Purnima;Srivastav, Supriya;Ukil, Anindita
通讯作者：
Ukil, Anindita
影响因子：
7.9
作者：
Cheng, Kur-Ta;Wang, Yu-Shiou;Juan, Shu-Hui
通讯作者：
Juan, Shu-Hui