The role of PPARβ/δ in human macrophages
Macrophages represent the most diverse cell type in biology. They adapt selectively to many stimuli allowing for precise functionality in any environment without harming the organism. Consequently, they monitor their surroundings carefully and react to a plethora of signals. Fatty acids and their de...
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|Macrophages represent the most diverse cell type in biology. They adapt selectively to many stimuli allowing for precise functionality in any environment without harming the organism. Consequently, they monitor their surroundings carefully and react to a plethora of signals. Fatty acids and their derivatives are important signaling mediators in this context, which besides other signals impinge on the lipid-regulated nuclear receptor peroxisome proliferator-activated receptor (PPARβ/δ).
Studies conducted in mice have shown that ablation of PPARβ/δ results in the inability of adipose and liver macrophages to adopt an alternative anti-inflammatory activation state, demonstrating a prominent role of PPARβ/δ in macrophage function with implications for immune regulation. To date, however, systematic studies focusing on PPARβ/δ's role in human macrophages have not been reported.
The first part of this thesis addresses the role of PPARβ/δ in human macrophages including its transcriptional network affecting a multitude of cellular processes. A major part of this network involves cell type independent canonical regulation, which is characterized by the binding of PPARβ/δ with its obligatory dimerization partner retinoid X receptor (RXR) to specific sites in the regulatory region of established and previously unreported target genes, their induction by agonists and repression by inverse agonists. Additionally, a new set of non-canonical regulated target genes is described. These genes lack chromatin-bound PPARβ/δ complexes, are repressed by agonists (inverse regulation) and are macrophage-selective. Consistent with the prevailing opinion and the induction of an IL4-like morphological phenotype by agonists, this mode of regulation inhibits pro-inflammatory signaling. Surprisingly, anti-inflammatory genes, such as CD32B, IDO1 and CD274 (PD-L1) were also repressed. Consistent with these results, immune functions such as CD8+ T cell activation were stimulated by these ligands. In combination, these findings point to a unique macrophage activation state induced by PPARβ/δ agonists with context dependent functions in immune regulation.
The second part describes the PPARβ/δ-regulated transcriptome for tumor-associated macrophages (TAMs) from human serous ovarian carcinoma ascites. Interestingly, most canonical PPARβ/δ target genes were found to be upregulated and refractory to synthetic agonists as compared to monocyte-derived macrophages. This was not due to a TAM specific increase in PPARβ/δ protein level or recruitment to target genes. However, the unaffected response of these genes to inverse agonists hinted at the presence of endogenous activating ligands. Lipidomic analysis of malignancy-associated ascites indeed revealed very high concentrations of dietary polyunsaturated fatty acids (PUFAs), mainly linoleic and arachidonic acid. These PUFAs induced lipid droplet formation in macrophages which provide a potential reservoir for PPARβ/δ agonists and may serve as the causal nexus for target gene deregulation. Among the deregulated genes, ANGPTL4 is associated with shorter relapse-free survival, illustrating the potential clinical implications of these findings