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• W2738954627 abstract "Nonalcoholic steatohepatitis (NASH) is a major complication in patients with obesity and type 2 diabetes, and can progress to cirrhosis, liver failure and death. No effective treatments exist. NASH is characterized by steatosis and increased numbers of inflammatory myeloid cells in the liver, and depletion of myeloid cells with toxic-liposomes reduces disease. Liposomes therefore offer a means to selectively target myeloid cells with compounds that inhibit inflammatory pathways. In this thesis I investigate whether anti-inflammatory compounds, encapsulated into 100 nm liposomes can target inflammatory myeloid cells, inhibit inflammatory pathways in myeloid cells and the outcome of this on liver disease. Two rodent NASH models were examined: an acute model where mice were fed methionine and choline deficient (MCD) diet for 3 weeks and a chronic model where mice were fed a high-fat high-sugar (HFHS) diet for 14 weeks. In the acute MCD model, mice developed severe steatohepatitis, with increased proportions of inflammatory myeloid cells. Intravenously injected curcumin liposomes targeted hepatic inflammatory myeloid cells including inflammatory DCs, macrophages and monocytes. RNA sequencing of mRNA from DCs that had taken up liposomes indicated that curcumin down regulated mRNA in the JNK-MAPK-pathway, upregulated mRNA associated with alternative macrophage activation, oxidative phosphorylation and retinoic acid production. Mice treated with curcumin liposomes had reduced liver damage, inflammation and steatosis compared with untreated mice. In the chronic model, mice fed HFHS diet developed insulin resistance and NASH associated with hepatic inflammation and liver fibrosis. Intravenous injection of curcumin and vitamin D3 liposomes, but not empty liposomes, reduced liver histological scores and liver fibrosis in mice fed HFHS diet. RNA sequencing of mRNA from livers of mice fed a HFHS diet identified upregulation of mRNA encoding proteins associated with extracellular matrix deposition, regulation of apoptosis and leukocyte recruitment and activation. Similar analysis of livers from mice treated with curcumin or vitamin D3 liposomes identified downregulation of mRNAs encoding proteins within these pathways. Finally, the role of regulatory T cells in NASH was investigated. Mice fed a MCD-diet for 3 weeks had increased proportions of regulatory T cells in the liver. Depletion of regulatory T cells exacerbated MCD-diet induced liver damage, steatosis and necroinflammation. Injection of ovalbumin and curcumin in a single liposome formulation induced proliferation of adoptively transferred ovalbumin specific CD4+ T cells in the liver and spleen. Furthermore, mice injected intravenously with ovalbumin/curcumin liposomes together with adoptively transferred ovalbumin specific regulatory T cells had reduced MCD-diet induced hepatocyte damage. Together these data indicate that anti-inflammatory drugs including curcumin and vitamin D3, encapsulated in liposomes, target hepatic inflammatory DCs, induce alternative/tolerogenic phenotype and prevent steatohepatitis progression to liver fibrosis. Curcumin liposomes coupled with ovalbumin, co-injected with ovalbumin-specific regulatory T cells has an additional therapeutic effect. These findings demonstrate the importance of both innate and adaptive immune cells in progression of liver disease and the feasibility of delivering anti-inflammatory drugs and antigen to these cells to treat NASH." @default.
• W2738954627 created "2017-07-31" @default.
• W2738954627 creator A5060667621 @default.
• W2738954627 date "2016-12-02" @default.
• W2738954627 modified "2023-09-27" @default.
• W2738954627 title "Targeting liver inflammatory myeloid cells with immunomodulatory liposomes improves nonalcoholic steatohepatitis in mice" @default.
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