PMID- 35066108 OWN - NLM STAT- MEDLINE DCOM- 20220425 LR - 20230310 IS - 1096-1186 (Electronic) IS - 1043-6618 (Print) IS - 1043-6618 (Linking) VI - 177 DP - 2022 Mar TI - Kinsenoside attenuates liver fibro-inflammation by suppressing dendritic cells via the PI3K-AKT-FoxO1 pathway. PG - 106092 LID - S1043-6618(22)00037-8 [pii] LID - 10.1016/j.phrs.2022.106092 [doi] AB - 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 CCl(4)-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 alpha-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. CI - Copyright (c) 2022 Elsevier Ltd. All rights reserved. FAU - Xiang, Ming AU - Xiang M AD - Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. FAU - Liu, Tingting AU - Liu T AD - Department of Pharmacy, the First Affiliated Hospital of Anhui Medical University, the Grade 3 Pharmaceutical Chemistry Laboratory of State Administration of Traditional Chinese Medicine, Hefei, Anhui, China. FAU - Tian, Cheng AU - Tian C AD - Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. FAU - Ma, Kun AU - Ma K AD - Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. FAU - Gou, Jing AU - Gou J AD - Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. FAU - Huang, Rongrong AU - Huang R AD - Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. FAU - Li, Senlin AU - Li S AD - Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. FAU - Li, Qing AU - Li Q AD - Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. FAU - Xu, Chuanrui AU - Xu C AD - Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. FAU - Li, Lei AU - Li L AD - Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. FAU - Lee, Chih-Hao AU - Lee CH AD - Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA, USA. FAU - Zhang, Yonghui AU - Zhang Y AD - Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. Electronic address: zhangyh@tjmu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220121 PL - Netherlands TA - Pharmacol Res JT - Pharmacological research JID - 8907422 RN - 0 (3-glucopyranosyloxybutanolide) RN - 0 (B7-H1 Antigen) RN - 0 (Forkhead Box Protein O1) RN - 0 (Foxo1 protein, mouse) RN - 0 (Monosaccharides) RN - 187348-17-0 (Interleukin-12) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - OL659KIY4X (4-Butyrolactone) SB - IM MH - 4-Butyrolactone/analogs & derivatives MH - Animals MH - B7-H1 Antigen MH - Dendritic Cells/metabolism MH - Forkhead Box Protein O1 MH - *Hepatitis MH - Inflammation/drug therapy MH - Interleukin-12 MH - Mice MH - Monosaccharides MH - *Phosphatidylinositol 3-Kinases/metabolism MH - Proto-Oncogene Proteins c-akt/metabolism PMC - PMC8776354 OTO - NOTNLM OT - 740 Y-P (PubChem CID:90488730) OT - Dendritic cell OT - Interleukin-12 OT - Kinsenoside OT - Kinsenoside (PubChem CID:10422896) OT - LY294002 (PubChem CID:3973) OT - Liver fibro-inflammation OT - PI3K-AKT-FoxO1 axis OT - Programmed cell death ligand 1 COIS- The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2022/01/24 06:00 MHDA- 2022/04/26 06:00 PMCR- 2022/01/21 CRDT- 2022/01/23 20:29 PHST- 2021/09/01 00:00 [received] PHST- 2022/01/16 00:00 [revised] PHST- 2022/01/18 00:00 [accepted] PHST- 2022/01/24 06:00 [pubmed] PHST- 2022/04/26 06:00 [medline] PHST- 2022/01/23 20:29 [entrez] PHST- 2022/01/21 00:00 [pmc-release] AID - S1043-6618(22)00037-8 [pii] AID - 106092 [pii] AID - 10.1016/j.phrs.2022.106092 [doi] PST - ppublish SO - Pharmacol Res. 2022 Mar;177:106092. doi: 10.1016/j.phrs.2022.106092. Epub 2022 Jan 21.