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( Kyurae Kim ),( Jun-hee Lee ),( Young-ri Shim ),( Hee-hoon Kim ),( Ye Eun Kim ),( Keungmo Yang ),( Tom Ryu ),( Won-il Jeong ) 대한간학회 2020 춘·추계 학술대회 (KASL) Vol.2020 No.1
Aims: Cluster of differentiation 40 (CD40) is a costimulatory molecule on antigen presenting cells including macrophages. An interesting study reported that extracellular vesicles (EVs) containing CD40L promote macrophage activation through CD40, thereby accelerating alcoholic liver diseases (ALD) in mice and patients. However, other effects of CD40L-expressing EV on Kupffer cells (KCs) have not been investigated clearly. Here, we explored CD40-mediated delivery of hepatic exosomes and its effects on KCs in acute alcoholic liver injury. Methods: To induce acute liver injury, binge ethanol drinking (4 g/kg, 40% ethanol) was performed by oral gavage into wildtype (WT) and CD40 knockout (KO) mice. Interleukin-17A (IL- 17A) positive cells were analyzed by flow cytometry. Isolated hepatocytes, KCs and DiI-stained exosomes, neutralizing antibody and dynasore were used for in vitro experiments. Results: Although the number of exosomes and mRNA expression of CD40L in hepatocytes were significantly increased by ethanol exposure, protein levels of CD40L in ethanol-induced exosomes were similar with controls, reflecting proportional increase of CD40L to the numbers of exosomes. However, freshly isolated KCs from ethanol-fed WT mice exhibited increased expression of CD40 (protein receptor of CD40L). In vitro, ethanol-induced exosomes increased CD40 expression in KCs by a TLR3-dependent manner. Moreover, DiI-stained exosomes were successfully delivered to WT KCs, but not in CD40-deficient KCs. In addition, treatments with neutralizing antibody of CD40 and dynamin inhibitor (dynasore) decreased internalization of hepatic exosomes into KCs, thereby reducing IL-1β production in KCs. Furthermore, binge ethanol drinking increased IL-17A production of γδ T cells in WT mice but not in CD40 KO mice. Conclusions: Alcohol-induced hepatic exosomes could be delivered to KCs through a CD40L/CD40-dependent endocytic uptake and they stimulate IL-1β expression in KCs, subsequently leading to IL-17A production in γδ T cells in ALD. Thus, CD40L/ CD40 axis could be a potential target to reduce IL-17A production in ALD.
Kim Hee-Hoon,Shim Young-Ri,Choi Sung Eun,Kim Myung-Ho,Lee Giljae,You Hyun Ju,Choi Won-Mook,Keungmo Yang,Ryu Tom,Kim Kyurae,김민정,Woo Chaerin,Chung Katherine Po Sin,Hong Song Hwa,Eun Hyuk Soo,Kim Seok-Hw 생화학분자생물학회 2023 Experimental and molecular medicine Vol.55 No.-
Chronic alcohol consumption often induces hepatic steatosis but rarely causes severe inflammation in Kupffer cells (KCs) despite the increased hepatic influx of lipopolysaccharide (LPS), suggesting the presence of a veiled tolerance mechanism. In addition to LPS, the liver is affected by several gut-derived neurotransmitters through the portal blood, but the effects of catecholamines on KCs have not been clearly explored in alcohol-associated liver disease (ALD). Hence, we investigated the regulatory roles of catecholamine on inflammatory KCs under chronic alcohol exposure. We discovered that catecholamine levels were significantly elevated in the cecum, portal blood, and liver tissues of chronic ethanol-fed mice. Increased catecholamines induced mitochondrial translocation of cytochrome P450 2E1 in perivenous hepatocytes expressing the β2-adrenergic receptor (ADRB2), leading to the enhanced production of growth differentiation factor 15 (GDF15). Subsequently, GDF15 profoundly increased ADRB2 expression in adjacent inflammatory KCs to facilitate catecholamine/ADRB2-mediated apoptosis. Single-cell RNA sequencing of KCs confirmed the elevated expression of Adrb2 and apoptotic genes after chronic ethanol intake. Genetic ablation of Adrb2 or hepatic Gdf15 robustly decreased the number of apoptotic KCs near perivenous areas, exacerbating alcohol-associated inflammation. Consistently, we found that blood and stool catecholamine levels and perivenous GDF15 expression were increased in patients with early-stage ALD along with an increase in apoptotic KCs. Our findings reveal a novel protective mechanism against ALD, in which the catecholamine/GDF15 axis plays a critical role in KC apoptosis, and identify a unique neuro-metabo-immune axis between the gut and liver that elicits hepatoprotection against alcohol-mediated pathogenic challenges.
Kyurae Kim,Myung-Ho Kim,Ji In Kang,Jong-In Baek,Byeong-Min Jeon,Ho Min Kim,Sun-Chang Kim,Won-Il Jeong 고려인삼학회 2024 Journal of Ginseng Research Vol.48 No.1
Background: Ginsenoside F2 (GF2), the protopanaxadiol-type constituent in Panax ginseng, has been reported toattenuate metabolic dysfunction-associated steatotic liver disease (MASLD). However, the mechanism of action isnot fully understood. Here, this study investigates the molecular mechanism by which GF2 regulates MASLDprogression through liver X receptor (LXR). Methods: To demonstrate the effect of GF2 on LXR activity, computational modeling of protein-ligand binding,Time-resolved fluorescence resonance energy transfer (TR-FRET) assay for LXR cofactor recruitment, andluciferase reporter assay were performed. LXR agonist T0901317 was used for LXR activation in hepatocytes andmacrophages. MASLD was induced by high-fat diet (HFD) feeding with or without GF2 administration in WT andLXRα / mice. Results: Computational modeling showed that GF2 had a high affinity with LXRα. LXRE-luciferase reporter assaywith amino acid substitution at the predicted ligand binding site revealed that the S264 residue of LXRα was thecrucial interaction site of GF2. TR-FRET assay demonstrated that GF2 suppressed LXRα activity by favoring thebinding of corepressors to LXRα while inhibiting the accessibility of coactivators. In vitro, GF2 treatments reducedT0901317-induced fat accumulation and pro-inflammatory cytokine expression in hepatocytes and macrophages,respectively. Consistently, GF2 administration ameliorated hepatic steatohepatitis and improved glucoseor insulin tolerance in WT but not in LXRα / mice. Conclusion: GF2 alters the binding affinities of LXRα coregulators, thereby interrupting hepatic steatosis andinflammation in macrophages. Therefore, we propose that GF2 might be a potential therapeutic agent for theintervention in patients with MASLD.
Young-Ri Shim,Hee-Hoon Kim,Keungmo Yang,Tom Ryu,Kyurae Kim,Sung Eun Choi,Minjeong Kim,Chae-Rin Woo,Young-Sun Lee,Won-Il Jeong 한국실험동물학회 2021 한국실험동물학회 학술발표대회 논문집 Vol.2021 No.7
Liver is challenged by diverse detrimental substances through multiple metabolic processes, but it is less prone to inflammation. In chronic alcohol consumption, although the migration of monocytes from bone marrow (BM) into liver is increased, alcoholic hepatitis rarely occurs. Thus, we investigated the sub-population of liver macrophages showing anti-inflammatory roles through single-cell RNA sequencing (scRNA-Seq) after chronic EtOH-feeding. Interestingly, in scRNA-seq and flow cytometry analyses of hepatic macrophages, the phenotype of Ly6Clow (anti-inflammatory) cells was dramatically altered by ethanol intake. In particular, they were highly expressed interleukin-1 type II receptor (IL-1R2), a decoy receptor of IL-1β. Intriguingly, IL-1R2+ Ly6Clow macrophages showed decreased CX3CR1 expression, which was confirmed not only in the liver, but also BM and blood, suggesting monocytes from BM affected by ethanol might migrate into the liver. We found that the Leptin Receptor+ mesenchymal stromal cells (LepR+ MSCs), which were located around blood vessels expressing CX3CL1 to hold CX3CR1+ macrophages, could express alcohol dehydrogenase to metabolize ethanol in BM. Ethanol metabolism in LepR+ MSCs was induced both production of chemokines (CXCL9 and 10) and the excretion of glutamate via cystine-glutamate anti-porter xCT to recruit and activate the CXCR3+ BM NK cells to produce interferon-γ in a metabotropic glutamate receptor 5 (mGluR5)-dependent manner. Indeed, IFN-γ production was significantly decreased in EtOH-fed mice when we depleted mGluR5 in NK cells. In turn, NK cell-derived IFN-γ down-regulated CX3CR1 expression in BM Ly6Clow monocytes, consequently induced egress of Ly6Clow monocytes into the blood and migration into the liver to suppress alcoholic inflammation. In conclusion, glutamate of LepR+ MSCs imposed egress license on anti-inflammatory IL-1R2+ Ly6Clow monocytes through NK cell-derived IFN-γ-mediated suppression of CX3CR1, suggesting a potential therapeutic inter-organ crosstalk between BM and liver in alcoholic liver disease.