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

Research output: Contribution to journalArticle

12 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)175-182
Number of pages8
JournalJournal of Hepatology
Volume60
Issue number1
DOIs
Publication statusPublished - 2014 Jan

Fingerprint

Natural Killer T-Cells
Leptin
Adipocytes
Hepatitis
Leptin Receptors
T-Lymphocytes
Mitogen-Activated Protein Kinases
Single-Domain Antibodies
Janus Kinase 2
Adipokines
Energy Metabolism
Insulin Resistance
Adipose Tissue
Hepatocytes
Flow Cytometry
Obesity
Cell Proliferation
Cytokines

Keywords

  • Adipokines
  • ConA
  • Immunology
  • Immunometabolism
  • Liver pathology

ASJC Scopus subject areas

  • Hepatology

Cite this

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

In: Journal of Hepatology, Vol. 60, No. 1, 01.2014, p. 175-182.

Research output: Contribution to journalArticle

Venken, K, Seeuws, S, Zabeau, L, Jacques, P, Decruy, T, Coudenys, J, Verheugen, E, Windels, F, Catteeuw, D, Drennan, M, Van Calenbergh, S, Lambrecht, BN, Yoshimura, A, Tavernier, J & Elewaut, D 2014, 'A bidirectional crosstalk between iNKT cells and adipocytes mediated by leptin modulates susceptibility for T cell mediated hepatitis', Journal of Hepatology, vol. 60, no. 1, pp. 175-182. https://doi.org/10.1016/j.jhep.2013.08.008
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. / A bidirectional crosstalk between iNKT cells and adipocytes mediated by leptin modulates susceptibility for T cell mediated hepatitis. In: Journal of Hepatology. 2014 ; Vol. 60, No. 1. pp. 175-182.
@article{80c787c876b340008d18c2cdaa47cc40,
title = "A bidirectional crosstalk between iNKT cells and adipocytes mediated by leptin modulates susceptibility for T cell mediated hepatitis",
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.",
keywords = "Adipokines, ConA, Immunology, Immunometabolism, Liver pathology",
author = "Koen Venken and Sylvie Seeuws and Lennart Zabeau and Peggy Jacques and Tine Decruy and Julie Coudenys and Eveline Verheugen and Fien Windels and Dominiek Catteeuw and Michael Drennan and {Van Calenbergh}, Serge and Lambrecht, {Bart N.} and Akihiko Yoshimura and Jan Tavernier and Dirk Elewaut",
year = "2014",
month = "1",
doi = "10.1016/j.jhep.2013.08.008",
language = "English",
volume = "60",
pages = "175--182",
journal = "Journal of Hepatology",
issn = "0168-8278",
publisher = "Elsevier",
number = "1",

}

TY - JOUR

T1 - A bidirectional crosstalk between iNKT cells and adipocytes mediated by leptin modulates susceptibility for T cell mediated hepatitis

AU - Venken, Koen

AU - Seeuws, Sylvie

AU - Zabeau, Lennart

AU - Jacques, Peggy

AU - Decruy, Tine

AU - Coudenys, Julie

AU - Verheugen, Eveline

AU - Windels, Fien

AU - Catteeuw, Dominiek

AU - Drennan, Michael

AU - Van Calenbergh, Serge

AU - Lambrecht, Bart N.

AU - Yoshimura, Akihiko

AU - Tavernier, Jan

AU - Elewaut, Dirk

PY - 2014/1

Y1 - 2014/1

N2 - 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.

AB - 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.

KW - Adipokines

KW - ConA

KW - Immunology

KW - Immunometabolism

KW - Liver pathology

UR - http://www.scopus.com/inward/record.url?scp=84890559372&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84890559372&partnerID=8YFLogxK

U2 - 10.1016/j.jhep.2013.08.008

DO - 10.1016/j.jhep.2013.08.008

M3 - Article

VL - 60

SP - 175

EP - 182

JO - Journal of Hepatology

JF - Journal of Hepatology

SN - 0168-8278

IS - 1

ER -