Muralidhara Rao Maradana1, Suman Kumar Yekollu1, Bijun Zeng1, Jonathan Ellis2, Andrew Clouston3, Gregory Miller3, Meghna Talekar1, Zaied Ahmed Bhuyan1, Sachin Mahadevaiah1, Elizabeth E Powell3, Katharine M Irvine3, Ranjeny Thomas4, Brendan John O'Sullivan5. 1. University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, Queensland 4102, Australia. 2. Queensland University of Technology, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, Queensland 4102, Australia. 3. Faculty of Medicine, The University of Queensland, Queensland 4102, Australia. 4. University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, Queensland 4102, Australia. Electronic address: ranjeny.thomas@uq.edu.au. 5. University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, Queensland 4102, Australia. Electronic address: b.osullivan1@uq.edu.au.
Abstract
OBJECTIVE: Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic macrophage inflammation, steatosis and fibrosis. Liposomes injected intravenously passively target hepatic myeloid cells and have potential to deliver immunomodulatory compounds and treat disease. We investigated targeting, delivery, immunomodulation and efficacy of liposomes in mice with diet-induced NASH. METHODS: Liposome-encapsulated lipophilic curcumin or 1,25-dihydroxy-vitamin D3 (calcitriol) were injected intravenously into mice with diet-induced NASH. Liver and cell liposome uptake was assessed by in vivo imaging and flow cytometry. Immunomodulation of targeted cells were assessed by RNA transcriptome sequencing. NASH was assessed by histological scoring, serum liver enzymes and fasting glucose/insulin and liver RNA transcriptome sequencing. RESULTS: Liposomes targeted lipid containing MHC class-II+ hepatic dendritic cells in mice and humans. Delivery of liposomal curcumin to hepatic dendritic cells shifted their inflammatory profile towards a regulatory phenotype. Delivery of liposomal curcumin or calcitriol to mice with diet-induced NASH led to reduced liver inflammation, fibrosis and fat accumulation, and reduced insulin resistance. RNA transcriptome sequencing of liver from treated mice identified suppression of pathways of immune activation, cell cycle and collagen deposition. CONCLUSIONS: Liposomes are a new strategy to target lipid rich inflammatory dendritic cells and have potential to deliver immunomodulatory compounds to treat NASH. Crown
OBJECTIVE:Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic macrophage inflammation, steatosis and fibrosis. Liposomes injected intravenously passively target hepatic myeloid cells and have potential to deliver immunomodulatory compounds and treat disease. We investigated targeting, delivery, immunomodulation and efficacy of liposomes in mice with diet-induced NASH. METHODS: Liposome-encapsulated lipophilic curcumin or 1,25-dihydroxy-vitamin D3 (calcitriol) were injected intravenously into mice with diet-induced NASH. Liver and cell liposome uptake was assessed by in vivo imaging and flow cytometry. Immunomodulation of targeted cells were assessed by RNA transcriptome sequencing. NASH was assessed by histological scoring, serum liver enzymes and fasting glucose/insulin and liver RNA transcriptome sequencing. RESULTS: Liposomes targeted lipid containing MHC class-II+ hepatic dendritic cells in mice and humans. Delivery of liposomal curcumin to hepatic dendritic cells shifted their inflammatory profile towards a regulatory phenotype. Delivery of liposomal curcumin or calcitriol to mice with diet-induced NASH led to reduced liver inflammation, fibrosis and fat accumulation, and reduced insulin resistance. RNA transcriptome sequencing of liver from treated mice identified suppression of pathways of immune activation, cell cycle and collagen deposition. CONCLUSIONS: Liposomes are a new strategy to target lipid rich inflammatory dendritic cells and have potential to deliver immunomodulatory compounds to treat NASH. Crown
Authors: Ryan Galea; Hendrik J Nel; Meghna Talekar; Xiao Liu; Joshua D Ooi; Megan Huynh; Sara Hadjigol; Kate J Robson; Yi Tian Ting; Suzanne Cole; Karyn Cochlin; Shannon Hitchcock; Bijun Zeng; Suman Yekollu; Martine Boks; Natalie Goh; Helen Roberts; Jamie Rossjohn; Hugh H Reid; Ben J Boyd; Ravi Malaviya; David J Shealy; Daniel G Baker; Loui Madakamutil; A Richard Kitching; Brendan J O'Sullivan; Ranjeny Thomas Journal: JCI Insight Date: 2019-09-19
Authors: Aisha Rafique; Anders Etzerodt; Jonas H Graversen; Søren K Moestrup; Frederik Dagnæs-Hansen; Holger Jon Møller Journal: Int J Nanomedicine Date: 2019-04-23