Heme oxygenase-1 mitigates liver injury and fibrosis via modulation of LNX1/Notch1 pathway in myeloid cells
Giacomo Canesin,
Linda Feldbrügge,
Guangyan Wei,
Lubica Janovicova,
Monika Janikova,
Eva Csizmadia,
Juliana Ariffin,
Andreas Hedblom,
Zachary T. Herbert,
Simon C. Robson,
Peter Celec,
Kenneth D. Swanson,
Imad Nasser,
Yury V. Popov,
Barbara Wegiel
Affiliations
Giacomo Canesin
Department of Surgery, Division of Surgical Sciences, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
Linda Feldbrügge
Charité – Universitätsmedizin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, 13353 Berlin, Germany; Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
Guangyan Wei
Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Radiation Oncology, First Affiliated Hospital, Sun Yat-sen University, 510080 Guangzhou, China
Lubica Janovicova
Department of Surgery, Division of Surgical Sciences, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Institute of Molecular Biomedicine, Comenius University in Bratislava, 811 08 Bratislava, Slovakia
Monika Janikova
Department of Surgery, Division of Surgical Sciences, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Institute of Molecular Biomedicine, Comenius University in Bratislava, 811 08 Bratislava, Slovakia
Eva Csizmadia
Department of Surgery, Division of Surgical Sciences, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
Juliana Ariffin
Department of Surgery, Division of Surgical Sciences, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
Andreas Hedblom
Department of Surgery, Division of Surgical Sciences, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
Zachary T. Herbert
Molecular Biology Core Facilities, Dana-Farber Cancer Institute, Boston, MA 02215, USA
Simon C. Robson
Department of Anesthesia, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
Peter Celec
Institute of Molecular Biomedicine, Comenius University in Bratislava, 811 08 Bratislava, Slovakia
Kenneth D. Swanson
Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
Imad Nasser
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
Yury V. Popov
Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Corresponding author
Barbara Wegiel
Department of Surgery, Division of Surgical Sciences, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Corresponding author
Summary: Activation of resident macrophages (Mϕ) and hepatic stellate cells is a key event in chronic liver injury. Mice with heme oxygenase-1 (HO-1; Hmox1)-deficient Mϕ (LysM-Cre:Hmox1flfl) exhibit increased inflammation, periportal ductular reaction, and liver fibrosis following bile duct ligation (BDL)-induced liver injury and increased pericellular fibrosis in NASH model. RiboTag-based RNA-sequencing profiling of hepatic HO-1-deficient Mϕ revealed dysregulation of multiple genes involved in lipid and amino acid metabolism, regulation of oxidative stress, and extracellular matrix turnover. Among these genes, ligand of numb-protein X1 (LNX1) expression is strongly suppressed in HO-1-deficient Mϕ. Importantly, HO-1 and LNX1 were expressed by hepatic Mϕ in human biliary and nonbiliary end-stage cirrhosis. We found that Notch1 expression, a downstream target of LNX1, was increased in LysM-Cre:Hmox1flfl mice. In HO-1-deficient Mϕ treated with heme, transient overexpression of LNX1 drives M2-like Mϕ polarization. In summary, we identified LNX1/Notch1 pathway as a downstream target of HO-1 in liver fibrosis.
