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

Koen Venken, Sylvie Seeuws, Lennart Zabeau, Peggy Jacques, Tine Decruy, Julie Coudenys, Eveline Verheugen, Fien Windels, Dominiek Catteeuw, Michael Drennan, Serge Van Calenbergh, Bart N. Lambrecht, Akihiko Yoshimura, Jan Tavernier, Dirk Elewaut

研究成果: Article査読

13 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)175-182
ページ数8
ジャーナルJournal of Hepatology
60
1
DOI
出版ステータスPublished - 2014 1

ASJC Scopus subject areas

  • Hepatology

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