A bidirectional crosstalk between iNKT cells and adipocytes mediated by leptin modulates susceptibility for T cell mediated hepatitis

• Published in: Journal of hepatology 2014-01, Vol.60 (1), p.175-182
• Main Authors: Venken, Koen, Seeuws, Sylvie, Zabeau, Lennart, Jacques, Peggy, Decruy, Tine, Coudenys, Julie, Verheugen, Eveline, Windels, Fien, Catteeuw, Dominiek, Drennan, Michael, Van Calenbergh, Serge, Lambrecht, Bart N, Yoshimura, Akihiko, Tavernier, Jan, Elewaut, Dirk
• Format: Article
• Language: English
• Subjects: Adipocytes - physiology; Adipokines; Adipose Tissue - metabolism; Animals; Cell Communication; ConA; Disease Susceptibility; Gastroenterology and Hepatology; Hepatitis - etiology; Immunology; Immunometabolism; Leptin - physiology; Liver pathology; Lymphocyte Activation; MAP Kinase Signaling System; Mice; Natural Killer T-Cells - physiology; Receptors, Antigen, T-Cell - physiology; Receptors, Leptin - physiology; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins - physiology; T-Lymphocytes - immunology
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2013.08.008

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.