Koen Venken1, Sylvie Seeuws1, Lennart Zabeau2, Peggy Jacques1, Tine Decruy1, Julie Coudenys1, Eveline Verheugen1, Fien Windels1, Dominiek Catteeuw2, Michael Drennan1, Serge Van Calenbergh3, Bart N Lambrecht4, Akihiko Yoshimura5, Jan Tavernier2, Dirk Elewaut6. 1. Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Faculty of Medicine and Health Sciences, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium. 2. Flanders Institute for Biotechnology, Department of Medical Protein Research, Faculty of Medicine and Health Sciences, Ghent University, A. Baertsoenkaai 3, 9000 Ghent, Belgium. 3. Laboratory for Medicinal Chemistry, Faculty of Pharmaceutical Sciences (FFW), Ghent University, Harelbekestraat 72, 9000 Ghent, Belgium. 4. Laboratory of Immunoregulation and Mucosal Immunology, Department of Molecular Biomedical Research, VIB and Ghent University, De Pintelaan 185, 9000 Ghent, Belgium. 5. Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo 160-8582, Japan; Japan Science and Technology Agency, CREST, Tokyo 102-0075, Japan. 6. Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Faculty of Medicine and Health Sciences, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium. Electronic address: dirk.elewaut@ugent.be.
Abstract
BACKGROUND & AIMS: Immunometabolism is an emerging field of clinical investigation due to the obesity epidemic worldwide. A reciprocal involvement of immune mediators in the body energy metabolism has been recognized for years, but is only partially understood. We hypothesized that the adipokine leptin could provide an important modulator of iNKT cells. METHODS: The expression of leptin receptor (LR) on resting and activated iNKT cells was measured by flow cytometry. FACS-sorted hepatic iNKT cells were stimulated with anti-CD3/CD28Ab coated beads in the absence or presence of a neutralizing anti-leptin Ab. Furthermore, we evaluated the outcome of LR blocking nanobody treatment in ConA induced hepatitis and towards metabolic parameters in WT and iNKT cell deficient mice. RESULTS: The LR is expressed on iNKT cells and leptin suppresses iNKT cell proliferation and cytokine production in vitro. LR deficient iNKT cells are hyper-responsive further enforcing the role of leptin as an important inhibitor of iNKT cell function. Consistently, in vivo blockade of LR signaling exacerbated ConA hepatitis in wild-type but not in iNKT cell deficient mice, through both Janus kinase (JAK)2 and mitogen-activated protein kinase (MAPK) dependent mechanisms. Moreover, LR inhibition altered fat pad features and was accompanied by insulin resistance, only in wild-type mice. Curiously, this interaction was strictly dependent on MAPK mediated LR signaling in iNKT cells and uncoupled from the more central effects of leptin. CONCLUSIONS: Our data support a new concept of immune regulation by which leptin protects towards T cell mediated hepatitis via modulation of iNKT cells.
BACKGROUND & AIMS: Immunometabolism is an emerging field of clinical investigation due to the obesity epidemic worldwide. A reciprocal involvement of immune mediators in the body energy metabolism has been recognized for years, but is only partially understood. We hypothesized that the adipokine leptin could provide an important modulator of iNKT cells. METHODS: The expression of leptin receptor (LR) on resting and activated iNKT cells was measured by flow cytometry. FACS-sorted hepatic iNKT cells were stimulated with anti-CD3/CD28Ab coated beads in the absence or presence of a neutralizing anti-leptin Ab. Furthermore, we evaluated the outcome of LR blocking nanobody treatment in ConA induced hepatitis and towards metabolic parameters in WT and iNKT cell deficient mice. RESULTS: The LR is expressed on iNKT cells and leptin suppresses iNKT cell proliferation and cytokine production in vitro. LR deficient iNKT cells are hyper-responsive further enforcing the role of leptin as an important inhibitor of iNKT cell function. Consistently, in vivo blockade of LR signaling exacerbated ConA hepatitis in wild-type but not in iNKT cell deficient mice, through both Janus kinase (JAK)2 and mitogen-activated protein kinase (MAPK) dependent mechanisms. Moreover, LR inhibition altered fat pad features and was accompanied by insulin resistance, only in wild-type mice. Curiously, this interaction was strictly dependent on MAPK mediated LR signaling in iNKT cells and uncoupled from the more central effects of leptin. CONCLUSIONS: Our data support a new concept of immune regulation by which leptin protects towards T cell mediated hepatitis via modulation of iNKT cells.
Authors: Francesca A Ververs; Suzanne E Engelen; Roos Nuboer; Bas Vastert; Cornelis K van der Ent; Belinda Van't Land; Johan Garssen; Claudia Monaco; Marianne Boes; Henk S Schipper Journal: Sci Rep Date: 2021-10-11 Impact factor: 4.379
Authors: Lennart Zabeau; Cathy J Jensen; Sylvie Seeuws; Koen Venken; Annick Verhee; Dominiek Catteeuw; Geert van Loo; Hui Chen; Ken Walder; Jacob Hollis; Simon Foote; Margaret J Morris; José Van der Heyden; Frank Peelman; Brian J Oldfield; Justin P Rubio; Dirk Elewaut; Jan Tavernier Journal: Cell Mol Life Sci Date: 2014-08-07 Impact factor: 9.261