The important roles of retinols and their metabolites have recently been emphasized in the interactions between hepatic stellate cells (HSCs) and natural killer (NK) cells. Nevertheless, the expression and role of retinol metabolizing enzyme in both cell types have yet to be clarified. Thus, we investigated the expression of retinol metabolizing enzyme and its role in liver fibrosis. Among several retinol metabolizing enzymes, only alcohol dehydrogenase (ADH) 3 expression was detected in isolated HSCs and NK cells, whereas hepatocytes express all of them. In vitro treatment with 4-methylpyrazole (4-MP), a broad ADH inhibitor, or depletion of the ADH3 gene down-regulated collagen and transforming growth factor-β1 (TGF-β1) gene expression, but did not affect α-smooth muscle actin gene expression in cultured HSCs. Additionally, in vitro, treatments with retinol suppressed NK cell activities, whereas inhibition of ADH3 enhanced interferon-γ (IFN-γ) production and cytotoxicity of NK cells against HSCs. In vivo, genetic depletion of the ADH3 gene ameliorated bile duct ligation- and carbon tetrachloride-induced liver fibrosis, in which a higher number of apoptotic HSCs and an enhanced activation of NK cells were detected. Freshly isolated HSCs from ADH3-deficient mice showed reduced expression of collagen and TGF-β1, but enhanced expression of IFN-γ was detected in NK cells from these mice compared with those of control mice. Using reciprocal bone marrow transplantation of wild-type and ADH3-deficient mice, we demonstrated that ADH3 deficiency in both HSCs and NK cells contributed to the suppressed liver fibrosis. Conclusion: ADH3 plays important roles in promoting liver fibrosis by enhancing HSC activation and inhibiting NK cell activity, and could be used as a potential therapeutic target for the treatment of liver fibrosis. (Hepatology 2014;60:1044–1053)

The expression of chemokine receptor CX₃CR1 is related to migration and signaling in cells of the monocyte-macrophage lineage. The precise roles of CX₃CR1 in the liver have been investigated but not clearly elucidated. Here, we investigated the roles of CX₃CR1 in hepatic macrophages and liver injury. Hepatic and splenic CX₃CR1^lowF4/80^low monocytes and CX₃CR1^lowCD16⁻ monocytes were differentiated into CX₃CR1^highF4/80^high or CX₃CR1^highCD16⁺ macrophages by co-culture with endothelial cells. Moreover, CX₃CL1 deficiency in human umbilical vein endothelial cells (HUVECs) attenuated the expression of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), whereas recombinant CX₃CL1 treatment reversed this expression in co-cultured monocytes. Upon treatment with clodronate liposome, hepatic F4/80^high macrophages were successfully depleted at day 2 and recovered similarly in CX₃CR1^+/GFP and CX₃CR1^GFP/GFP mice at week 4, suggesting a CX₃CR1-independent replacement. However, F4/80^high macrophages of CX₃CR1^+/GFP showed a stronger pro-inflammatory phenotype than CX₃CR1^GFP/GFP mice. In clodronate-treated chimeric CX₃CR1^+/GFP and CX₃CR1^GFP/GFP mice, CX₃CR1⁺F4/80^high macrophages showed higher expression of IL-1β and TNF-α than CX₃CR1⁻F4/80^high macrophages. In alcoholic liver injury, despite the similar frequency of hepatic F4/80^high macrophages, CX₃CR1^GFP/GFP mice showed reduced liver injury, hepatic fat accumulation, and inflammatory responses than CX₃CR1^+/GFP mice. Thus, CX₃CR1 could be a novel therapeutic target for pro-inflammatory macrophage-mediated liver injury.

Aging is characterized by a progressive decline or loss of physiological functions, leading to increased susceptibility to disease or death. Several aging hallmarks, including genomic instability, cellular senescence, and mitochondrial dysfunction, have been suggested, which often lead to the numerous aging disorders. The periodontium, a complex structure surrounding and supporting the teeth, is composed of the gingiva, periodontal ligament, cementum, and alveolar bone. Supportive and protective roles of the periodontium are very critical to sustain life, but the periodontium undergoes morphological and physiological changes with age. In this review, we summarize the current knowledge of molecular and cellular physiological changes in the periodontium, by focusing on soft tissues including gingiva and periodontal ligament.

Recently, beneficial roles of ginsenoside F2 (GF2), a minor constituent of Panax ginseng, have been demonstrated in diverse inflammatory diseases. However, its roles in alcoholic liver inflammation and injury have not been clearly understood. Here, we investigated the underlying mechanism by which GF2 ameliorated alcoholic liver injury. To induce alcoholic liver injury, C57BL/6J wild type (WT) or interleukin (IL)-10 knockout (KO) mice were orally administered with ethanol (3 g/kg) or ethanol-containing GF2 (50 mg/kg) for 2 wk. Liver injury and infiltration of macrophages and neutrophils were evaluated by serum biochemistry and immunohistochemistry, respectively. The changes of hepatic immune cells were assessed by flow cytometry and polymerase chain reaction analysis. In vitro differentiation of naïve T cells was performed. GF2 treatment significantly attenuated alcoholic liver injury, in which infiltrations of inflammatory macrophages and neutrophils were decreased. Moreover, the frequencies of Foxp3+ regulatory T cells (Tregs) increased but IL-17–producing T (Th17) cells decreased in GF2-treated mice compared to controls. Furthermore, the mRNA expression of IL-10 and Foxp3 was significantly increased, whereas IL-17 mRNA expression was suppressed in GF2-treated mice. However, these beneficial roles of GF2 were not observed in GF2-treated IL-10 KO mice, suggesting a critical role of IL-10. Similarly, GF2 treatment suppressed differentiation of naïve T cells into Th17 cells by inhibiting RORγt expression and stimulating Foxp3 expression. The present study suggests that GF2 treatment attenuates alcoholic liver injury by increasing IL-10 expression and Tregs and decreasing IL-17 expression and Th17 cells.

Background and Aims: HSCs contribute to HCC progression by regulating multiple factors. However, the entire immunoregulatory functions of HSCs are still obscure. Here, we aim to investigate whether HSCs impose CX₃CR1⁺ macrophages to protumorigenic properties in the peritumoral area. Approach and Results: In single-cell RNA-sequencing analysis of patients with HCC, a subpopulation of macrophages specifically expressed Arg1 and Cx3cr1 in the peritumoral area and were highly enriched with retinol metabolism–related genes. Flow cytometry analysis showed significantly increased frequencies of CD14⁺CD11b⁺HLA-DR⁻ macrophages with CX₃CR1 in the HCC adjacent region where α-smooth muscle actin–expressing activated hepatic stellate cells (aHSCs) showed colocalized expression of CX₃CL1. Accordingly, in tumor-bearing mice, Cx3cl1 mRNA expression was notably increased in aHSCs within the adjacent HCC, where infiltration of CX₃CR1⁺Ly6C⁺ macrophages was mostly observed with decreased CD8⁺ T cells. In adoptive transfer and in vitro coculture of myeloid cells, we demonstrated that CX₃CR1⁺Ly6C⁺ macrophages migrated and highly expressed arginase-1 by interacting with retinoid-enriched aHSCs in the adjacent HCC. Direct treatment of retinoids or coculturing with retinol-storing mouse aHSCs or human LX-2 cells significantly increased arginase-1 expression in CX₃CR1⁺Ly6C⁺ macrophages and human blood CD14⁺ cells, leading to the suppression of CD8⁺ T-cell proliferation. Moreover, genetic deficiency of CX₃CR1 in myeloid cells or pharmacological inhibition of retinol metabolism remarkably attenuated HCC development. Conclusions: We showed that CX₃CR1⁺Ly6C⁺ macrophages migrate and interact with aHSCs in the peritumoral region where retinoids induce arginase-1 expression in CX₃CR1⁺Ly6C⁺ macrophages, subsequently depriving CD8⁺ T cells of arginine and promoting HCC.

Head and neck squamous cell carcinoma (HNSCC) is a highly aggressive and devastating disease arising primarily from the mucosal epithelium of the oral cavity, pharynx, and larynx. HNSCC ranks as the sixth most common cancer w... | Find, read and cite all the research you need on Tech Science Press