Olivier Robert1, Hédia Boujedidi1, Amélie Bigorgne1, Gladys Ferrere1, Cosmin Sebastian Voican2, Sabine Vettorazzi3, Jan Peter Tuckermann3, Laurence Bouchet-Delbos4, Thi Tran4, Patrice Hemon4, Virginie Puchois1, Ibrahim Dagher5, Richard Douard6, Francoise Gaudin7, Hélène Gary-Gouy8, Francis Capel4, Ingrid Durand-Gasselin4, Sophie Prévot9, Sophie Rousset4, Sylvie Naveau2, Véronique Godot1, Dominique Emilie1, Marc Lombès10, Gabriel Perlemuter11, Anne-Marie Cassard12. 1. INSERM UMR996 - Inflammation, Chemokines and Immunopathology, Clamart, France; Univ Paris-Sud, Univ Paris-Saclay, DHU Hepatinov, Labex Lermit, Kremlin-Bicêtre, France. 2. AP-HP, Hôpital Antoine-Béclère, Service d'hépato-gastroentérologie, Clamart, France. 3. Institute of Comparative Molecular Endocrinology (CME), Ulm University, 89081 Ulm, Germany. 4. INSERM UMR996 - Inflammation, Chemokines and Immunopathology, Clamart, France. 5. Univ Paris-Sud, Univ Paris-Saclay, DHU Hepatinov, Labex Lermit, Kremlin-Bicêtre, France; AP-HP, Hôpital Antoine-Béclère, Service de chirurgie minimale invasive, DHU Hépatinov, Clamart, France. 6. AP-HP, Hôpital Européen Georges Pompidou, Service de chirurgie, Paris, France; AP-HP, Hôpital Avicenne, Service de chirurgie, Bobigny, France. 7. INSERM UMR996 - Inflammation, Chemokines and Immunopathology, Clamart, France; IFR 141 Institut Paris-Sud d'Innovation Thérapeutique, Châtenay-Malabry, France. 8. IFR 141 Institut Paris-Sud d'Innovation Thérapeutique, Châtenay-Malabry, France. 9. AP-HP, Hôpital Antoine-Béclère, Service d'anatomie pathologique, Clamart, France. 10. Univ Paris-Sud, Univ Paris-Saclay, DHU Hepatinov, Labex Lermit, Kremlin-Bicêtre, France; INSERM, U693, Le Kremlin-Bicêtre, France; AP-HP, Hôpital Antoine-Béclère, Service d'anatomie pathologique, Clamart, France; AP-HP, Hôpital Bicêtre, Service d'Endocrinologie et Maladies de la Reproduction, Le Kremlin-Bicêtre, France. 11. INSERM UMR996 - Inflammation, Chemokines and Immunopathology, Clamart, France; Univ Paris-Sud, Univ Paris-Saclay, DHU Hepatinov, Labex Lermit, Kremlin-Bicêtre, France; AP-HP, Hôpital Antoine-Béclère, Service d'hépato-gastroentérologie, Clamart, France. Electronic address: gabriel.perlemuter@aphp.fr. 12. INSERM UMR996 - Inflammation, Chemokines and Immunopathology, Clamart, France; Univ Paris-Sud, Univ Paris-Saclay, DHU Hepatinov, Labex Lermit, Kremlin-Bicêtre, France. Electronic address: cassard.doulcier@u-psud.fr.
Abstract
BACKGROUND & AIMS: Kupffer cells (KC) play a key role in the onset of inflammation in non-alcoholic steatohepatitis (NASH). The glucocorticoid receptor (GR) induces glucocorticoid-induced leucine zipper (GILZ) expression in monocytes/macrophages and is involved in several inflammatory processes. We hypothesized that the GR-GILZ axis in KC may contribute to the pathophysiology of obesity-induced liver inflammation. METHODS: By using a combination of primary cell culture, pharmacological experiments, mice deficient for the Gr specifically in macrophages and transgenic mice overexpressing Gilz in macrophages, we explored the involvement of the Gr-Gilz axis in KC in the pathophysiology of obesity-induced liver inflammation. RESULTS: Obesity was associated with a downregulation of the Gr and Gilz, and an impairment of Gilz induction by lipopolysaccharide (LPS) and dexamethasone (DEX) in KC. Inhibition of Gilz expression in isolated KC transfected with Gilz siRNA demonstrated that Gilz downregulation was sufficient to sensitize KC to LPS. Conversely, liver inflammation was decreased in obese transgenic mice specifically overexpressing Gilz in macrophages. Pharmacological inhibition of the Gr showed that impairment of Gilz induction in KC by LPS and DEX in obesity was driven by a downregulation of the Gr. In mice specifically deficient for Gr in macrophages, Gilz expression was low, leading to an exacerbation of obesity-induced liver inflammation. CONCLUSIONS: Obesity is associated with a downregulation of the Gr-Gilz axis in KC, which promotes liver inflammation. The Gr-Gilz axis in KC is an important target for the regulation of liver inflammation in obesity.
BACKGROUND & AIMS: Kupffer cells (KC) play a key role in the onset of inflammation in non-alcoholic steatohepatitis (NASH). The glucocorticoid receptor (GR) induces glucocorticoid-induced leucine zipper (GILZ) expression in monocytes/macrophages and is involved in several inflammatory processes. We hypothesized that the GR-GILZ axis in KC may contribute to the pathophysiology of obesity-induced liver inflammation. METHODS: By using a combination of primary cell culture, pharmacological experiments, mice deficient for the Gr specifically in macrophages and transgenic mice overexpressing Gilz in macrophages, we explored the involvement of the Gr-Gilz axis in KC in the pathophysiology of obesity-induced liver inflammation. RESULTS:Obesity was associated with a downregulation of the Gr and Gilz, and an impairment of Gilz induction by lipopolysaccharide (LPS) and dexamethasone (DEX) in KC. Inhibition of Gilz expression in isolated KC transfected with Gilz siRNA demonstrated that Gilz downregulation was sufficient to sensitize KC to LPS. Conversely, liver inflammation was decreased in obesetransgenic mice specifically overexpressing Gilz in macrophages. Pharmacological inhibition of the Gr showed that impairment of Gilz induction in KC by LPS and DEX in obesity was driven by a downregulation of the Gr. In mice specifically deficient for Gr in macrophages, Gilz expression was low, leading to an exacerbation of obesity-induced liver inflammation. CONCLUSIONS:Obesity is associated with a downregulation of the Gr-Gilz axis in KC, which promotes liver inflammation. The Gr-Gilz axis in KC is an important target for the regulation of liver inflammation in obesity.
Authors: Joseph S Marino; Lance A Stechschulte; David E Stec; Andrea Nestor-Kalinoski; Sydni Coleman; Terry D Hinds Journal: J Biol Chem Date: 2016-10-26 Impact factor: 5.157
Authors: Detlef Schuppan; Henning Grønbæk; Konstantin Kazankov; Simon Mark Dahl Jørgensen; Karen Louise Thomsen; Holger Jon Møller; Hendrik Vilstrup; Jacob George Journal: Nat Rev Gastroenterol Hepatol Date: 2019-03 Impact factor: 46.802