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Front Immunol. 2019 Aug 9;10:1769. doi: 10.3389/fimmu.2019.01769. eCollection 2019.

Mechanisms Underlying the Functional Cooperation Between PPARα and GRα to Attenuate Inflammatory Responses.

Bougarne N1,2,3, Mylka V1,2,3, Ratman D1,2,3, Beck IM1,2,3,4,5,6,7, Thommis J1,2,3, De Cauwer L1,2,3, Tavernier J2,3,4, Staels B5, Libert C6,7, De Bosscher K1,2,3.

Author information

1
Translational Nuclear Receptor Research Lab, Ghent, Belgium.
2
Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.
3
VIB Center for Medical Biotechnology, Ghent, Belgium.
4
Receptor Research Laboratories, Cytokine Receptor Lab, Ghent, Belgium.
5
Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011 - EGID, Lille, France.
6
Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
7
VIB Center for Inflammation Research, Ghent, Belgium.

Abstract

Glucocorticoids (GCs) act via the glucocorticoid receptor (NR3C1, GRα) 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). PPARα (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 PPARα 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 GRα and PPARα. 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, GRα, and PPARα. Finally, to study metabolic effector target cells common to both receptors, we overlaid the effect of GRα and PPARα 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:

GRα; MSK1; PPARα; crosstalk; inflammation; molecular mechanism

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