Impact Factor 4.716 | CiteScore 4.71
More on impact ›

Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2019.01769

Mechanisms underlying the functional cooperation between PPARalpha and GRalpha to attenuate inflammatory responses

 Nadia Bougarne1, Mylka Viacheslav2, 3, Dariusz Ratman1, Ilse M. Beck4, Jonathan Thommis5, Lode De Cauwer6,  Bart STAELS7,  Jan Tavernier3, 8,  Claude Libert9 and  Karolien De Bosscher3, 10*
  • 1Department of biomolecular medicine, Ghent University, Belgium
  • 2Translational Nuclear Receptor Research lab, Department of Biomolecular Medicine, Ghent University, Belgium
  • 3VIB-UGent Center for Medical Biotechnology, Belgium
  • 4Lab Experimental Cancer Research, Ghent University, Belgium
  • 5Translational nuclear receptor research, UGent-VIB, Belgium
  • 6Department of biomolecular medicine, Flanders Institute for Biotechnology, Belgium
  • 7Institut Pasteur de Lille, U1011 - EGID, Université de Lille, France
  • 8Cytokine Receptor Lab, Department of Biomolecular Medicine, Ghent University, Belgium
  • 9Inflammation Research Center, Flanders Institute for Biotechnology, Belgium
  • 10biochemistry, Ghent University, Belgium

Glucocorticoids (GCs) act via the glucocorticoid receptor (NR3C1, GRalpha) to combat overshooting responses to infectious stimuli, including lipopolysaccharide (LPS). As such, GCs inhibit the activity of downstream effector cytokines, such as tumor necrosis factor (TNF). PPARalpha (NR1C1) is a nuclear receptor described to function on the crossroad between lipid metabolism and control of inflammation. In the current work, we have investigated the molecular mechanism by which GCs and PPARalpha agonists cooperate to jointly inhibit NF-κB-driven expression in A549 cells. We discovered a nuclear mechanism that predominantly targets Mitogen- and Stress-activated protein Kinase-1 activation upon co-triggering GRalpha and PPARalpha. In vitro GST-pull down data further support that the anti-inflammatory mechanism may additionally involve a non-competitive physical interaction between the p65 subunit of NF-κB, GRalpha and PPARalpha. Finally, to study metabolic effector target cells common to both receptors, we overlaid the effect of GRalpha and PPARalpha crosstalk in mouse primary hepatocytes under LPS-induced inflammatory conditions on a genome-wide level. RNA-seq results revealed lipid metabolism genes that were upregulated and inflammatory genes that were additively downregulated. Validation at the cytokine protein level finally supported a consistent additive anti-inflammatory response in hepatocytes.

Keywords: PPARalpha, GRalpha., crosstalk, molecular mechanism, Inflammation, MSK1

Received: 16 Apr 2019; Accepted: 12 Jul 2019.

Edited by:

Christoph Thiemermann, Queen Mary University of London, United Kingdom

Reviewed by:

Massimo Collino, University of Turin, Italy
Soile Tapio, Helmholtz Center Munich, Germany  

Copyright: © 2019 Bougarne, Viacheslav, Ratman, Beck, Thommis, De Cauwer, STAELS, Tavernier, Libert and De Bosscher. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Karolien De Bosscher, Ghent University, biochemistry, Ghent, 9000, Belgium, Karolien.DeBosscher@ugent.be