Activation of Proliferator-activated Receptors α and γ Induces Apoptosis of Human Monocyte-derived Macrophages

TLDR

Peroxisome proliferator‑activated receptors (PPARs) are key regulators of lipid and glucose metabolism and have been linked to metabolic disorders such as obesity, diabetes, and atherosclerosis. The study aimed to determine whether PPARα and PPARγ are expressed in differentiated human monocyte‑derived macrophages, which play roles in inflammation control and plaque formation. The authors examined the expression and subcellular localization of PPARα and PPARγ in these macrophages and assessed their transcriptional activity following ligand stimulation. Ligand activation of PPARγ, but not PPARα, induced apoptosis in resting macrophages, while both ligands triggered apoptosis in TNFα/IFNγ‑activated cells, and PPARγ inhibited NFκB p65/RelA transcriptional activity, revealing a novel anti‑apoptotic regulatory function of PPARs in macrophages with implications for inflammation and atherosclerosis.

Abstract

Peroxisome proliferator-activated receptors (PPARs) have been implicated in metabolic diseases, such as obesity, diabetes, and atherosclerosis, due to their activity in liver and adipose tissue on genes involved in lipid and glucose homeostasis. Here, we show that the PPARα and PPARγ forms are expressed in differentiated human monocyte-derived macrophages, which participate in inflammation control and atherosclerotic plaque formation. Whereas PPARα is already present in undifferentiated monocytes, PPARγ expression is induced upon differentiation into macrophages. Immunocytochemistry analysis demonstrates that PPARα resides constitutively in the cytoplasm, whereas PPARγ is predominantly nuclear localized. Transient transfection experiments indicate that PPARα and PPARγ are transcriptionally active after ligand stimulation. Ligand activation of PPARγ, but not of PPARα, results in apoptosis induction of unactivated differentiated macrophages as measured by the TUNEL assay and the appearance of the active proteolytic subunits of the cell death protease caspase-3. However, both PPARα and PPARγ ligands induce apoptosis of macrophages activated with tumor necrosis factor α/interferon γ. Finally, PPARγ inhibits the transcriptional activity of the NFκB p65/RelA subunit, suggesting that PPAR activators induce macrophage apoptosis by negatively interfering with the anti-apoptotic NFκB signaling pathway. These data demonstrate a novel function of PPAR in human macrophages with likely consequences in inflammation and atherosclerosis.