Parsing the Role of PPARs in Macrophage Processes

Abstract

Cells are richly equipped with nuclear receptors, which act as ligand-regulated transcription factors. Peroxisome proliferator activated receptors (PPARs), members of the nuclear receptor family, have been extensively studied for their roles in development, differentiation, and homeostatic processes. In the recent past, there has been substantial interest in understanding and defining the functions of PPARs and their agonists in regulating innate and adaptive immune responses as well as their pharmacologic potential in combating acute and chronic inflammatory disease. In this review, we focus on emerging evidence of the potential roles of the PPAR subtypes in macrophage biology. We also discuss the roles of dual and pan PPAR agonists as modulators of immune cell function, microbial infection, and inflammatory diseases.

Keywords: PPAR; PPAR a; PPAR agonist; PPAR γ; inflammatory disease; macrophage.

Figure 1

PPAR isoforms and their transcriptional regulatory function. (A) A schematic of the domain architect of PPAR isoforms PPARα, PPARβ/δ and PPARγ. (B) Cartoon showing ligand binding site in PPARs. (C) Ligand independent and dependent transcriptional regulatory mechanism of PPARs.

Figure 2

Role of PPARs in bacteria-induced inflammatory signaling. (A) Schematic illustrating LPS/bacteria induced inflammatory signal promoting transcription factors. Whereas PPARs interacts with and modulates transcription factors involved in microbe induced inflammation. (B) Schematic depicting gene expression of PPARs during infection. PPARA level is higher during inflammatory phase whereas PPARG is higher during resolution phase.

Figure 3

PPARs and tissue-resident macrophage. The schematics depicts the lineage determining role of PPARs in tissue resident macrophage, showing PPARG but not PPARA is major transcription that contributes towards defining the tissue-resident macrophage.

Figure 4

PPARs in macrophage function and polarization. The schematics depicts the biochemical steps involved in glycolysis and glucogenesis, and how each pathway correlates to different immune states of macrophages. PPARA regulates immune reactive state, glycolysis dominant state (red left side) and PPARG regulates immune tolerant state, gluconeogenesis dominant state (blue right side).

Figure 5

PPARα Inflammatory Pathways. This schematic visualizes how PPARα directly and indirectly influences inflammatory pathways using color coded lines and arrows labeled in the box in the bottom left.

Figure 6

PPARγ Inflammatory Pathways. This schematic visualizes how PPARγ directly and indirectly influences inflammatory pathways using color coded lines and arrows labeled in the box in the bottom left.