The transcriptional PPARβ/δ network in human macrophages defines a unique agonist-induced activation state.
Peroxisome proliferator-activated receptor β/δ (PPARβ/δ) is a lipid ligand-inducible transcription factor with established metabolic functions, whereas its anti-inflammatory function is poorly understood. To address this issue, we determined the global PPARβ/δ-regulated signaling network in human monocyte-derived macrophages. Besides cell type-independent, canonical target genes with metabolic and immune regulatory functions we identified a large number of inflammation-associated NFκB and STAT1 target genes that are repressed by agonists. Accordingly, PPARβ/δ agonists inhibited the expression of multiple pro-inflammatory mediators and induced an anti-inflammatory, IL-4-like morphological phenotype. Surprisingly, bioinformatic analyses also identified immune stimulatory effects. Consistent with this prediction, PPARβ/δ agonists enhanced macrophage survival under hypoxic stress and stimulated CD8(+) T cell activation, concomitantly with the repression of immune suppressive target genes and their encoded products CD274 (PD-1 ligand), CD32B (inhibitory Fcγ receptor IIB) and indoleamine 2,3-dioxygenase 1 (IDO-1), as well as a diminished release of the immune suppressive IDO-1 metabolite kynurenine. Comparison with published data revealed a significant overlap of the PPARβ/δ transcriptome with coexpression modules characteristic of both anti-inflammatory and pro-inflammatory cytokines. Our findings indicate that PPARβ/δ agonists induce a unique macrophage activation state with strong anti-inflammatory but also specific immune stimulatory components, pointing to a context-dependent function of PPARβ/δ in immune regulation.
Institute of Molecular Biology and Tumor Research (IMT), Center for Tumor Biology and Immunology (ZTI), Philipps University, 35043 Marburg, Germany.
Till
T
Adhikary
Institute of Molecular Biology and Tumor Research (IMT), Center for Tumor Biology and Immunology (ZTI), Philipps University, 35043 Marburg, Germany.
Annika
A
Wortmann
Institute of Molecular Biology and Tumor Research (IMT), Center for Tumor Biology and Immunology (ZTI), Philipps University, 35043 Marburg, Germany.
Tim
T
Schumann
Institute of Molecular Biology and Tumor Research (IMT), Center for Tumor Biology and Immunology (ZTI), Philipps University, 35043 Marburg, Germany.
Florian
F
Finkernagel
Institute of Molecular Biology and Tumor Research (IMT), Center for Tumor Biology and Immunology (ZTI), Philipps University, 35043 Marburg, Germany.
Sonja
S
Lieber
Cellular Imaging Core Facility, Philipps University, Center for Tumor Biology and Immunology (ZTI), 35043 Marburg, Germany.
Katrin
K
Roth
Medicinal Chemistry Core Facility and Institute of Pharmaceutical Chemistry, Center for Tumor Biology and Immunology (ZTI), Philipps University, 35043 Marburg, Germany.
Philipp M
PM
Toth
Medicinal Chemistry Core Facility and Institute of Pharmaceutical Chemistry, Center for Tumor Biology and Immunology (ZTI), Philipps University, 35043 Marburg, Germany.
Wibke E
WE
Diederich
Genomics Core Facility, Center for Tumor Biology and Immunology (ZTI), Philipps University, 35043 Marburg, Germany.
Andrea
A
Nist
Genomics Core Facility, Center for Tumor Biology and Immunology (ZTI), Philipps University, 35043 Marburg, Germany.
Thorsten
T
Stiewe
Clinic for Gynecology, Gynecological Oncology and Gynecological Endocrinology, Center for Tumor Biology and Immunology (ZTI), Philipps University, 35043 Marburg, Germany.
Lara
L
Kleinesudeik
Clinic for Gynecology, Gynecological Oncology and Gynecological Endocrinology, Center for Tumor Biology and Immunology (ZTI), Philipps University, 35043 Marburg, Germany.
Silke
S
Reinartz
Institute of Molecular Biology and Tumor Research (IMT), Center for Tumor Biology and Immunology (ZTI), Philipps University, 35043 Marburg, Germany.
Sabine
S
Müller-Brüsselbach
Institute of Molecular Biology and Tumor Research (IMT), Center for Tumor Biology and Immunology (ZTI), Philipps University, 35043 Marburg, Germany rmueller@imt.uni-marburg.de.
Rolf
R
Müller
D002454:Cell Differentiation; D002460:Cell Line; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006801:Humans; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D047494:PPAR delta / Q000819:agonists / Q000378:metabolism*; D048068:PPAR-beta / Q000819:agonists / Q000378:metabolism*; D059467:Transcriptome
D047494:PPAR delta; D048068:PPAR-beta