title: Antibody-Directed Glucocorticoid Targeting to CD163 in M2-type Macrophages Attenuates Fructose-Induced Liver Inflammatory Changes.
abstract: Increased consumption of high-caloric carbohydrates contributes substantially to endemic non-alcoholic fatty liver disease in humans, covering a histological spectrum from fatty liver to steatohepatitis. Hypercaloric intake and lipogenetic effects of fructose and endotoxin-driven activation of liver macrophages are suggested to be essential to disease progression. In the present study, we show that a low dose of an anti-CD163-IgG-dexamethasone conjugate targeting the hemoglobin scavenger receptor CD163 in Kupffer cells and other M2-type macrophages has a profound effect on liver inflammatory changes in rats on a high-fructose diet. The diet induced severe non-alcoholic steatohepatitis (NASH)-like changes within a few weeks but the antibody-drug conjugate strongly reduced inflammation, hepatocyte ballooning, fibrosis, and glycogen deposition. Non-conjugated dexamethasone or dexamethasone conjugated to a control IgG did not have this effect but instead exacerbated liver lipid accumulation. The low-dose anti-CD163-IgG-dexamethasone conjugate displayed no apparent systemic side effects. In conclusion, macrophage targeting by antibody-directed anti-inflammatory low-dose glucocorticoid therapy seems to be a promising approach for safe treatment of fructose-induced liver inflammation.
authors.affiliation: Department of Molecular Medicine, University of Southern Denmark, 5000 Odense, Denmark.
authors.forename: Pia
authors.initials: P
authors.lastname: Svendsen
authors.affiliation: Department of Molecular Medicine, University of Southern Denmark, 5000 Odense, Denmark.
authors.forename: Jonas H
authors.initials: JH
authors.lastname: Graversen
authors.affiliation: Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark; Centre d'Immunologie de Marseille-Luminy (CIML), 13009 Marseille, France.
authors.forename: Anders
authors.initials: A
authors.lastname: Etzerodt
authors.affiliation: Department of Pathology, Vejle Hospital, University of Southern Denmark, 5000 Odense, Denmark.
authors.forename: Henrik
authors.initials: H
authors.lastname: Hager
authors.affiliation: Department of Pathology, Aalborg University Hospital, 9100 Aalborg, Denmark.
authors.forename: Rasmus
authors.initials: R
authors.lastname: Røge
authors.affiliation: Department of Hepatology, Aarhus University Hospital, 8000 Aarhus, Denmark.
authors.forename: Henning
authors.initials: H
authors.lastname: Grønbæk
authors.affiliation: Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark.
authors.forename: Erik I
authors.initials: EI
authors.lastname: Christensen
authors.affiliation: Department of Clinical Biochemistry, Aarhus University Hospital, 8000 Aarhus, Denmark.
authors.forename: Holger J
authors.initials: HJ
authors.lastname: Møller
authors.affiliation: Department of Hepatology, Aarhus University Hospital, 8000 Aarhus, Denmark.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Vilstrup
authors.affiliation: Department of Molecular Medicine, University of Southern Denmark, 5000 Odense, Denmark; Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark; Department of Clinical Biochemistry, Aarhus University Hospital, 8000 Aarhus, Denmark; Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, 5000 Odense, Denmark.
authors.forename: Søren K
authors.initials: SK
authors.lastname: Moestrup
keywords: CD163; antibody-drug conjugates; dexamethasone; fructose; glucocorticoid; inflammation; macrophages; steatohepatitis