Targeting liver inflammatory myeloid cells with immunomodulatory liposomes improves nonalcoholic steatohepatitis in mice

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 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.