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.

Protection against influenza-induced Acute Lung Injury (ALI) by enhanced induction of M2a macrophages: possible role of PPARγ/RXR ligands in IL-4-induced M2a macrophage differentiation

“…PPARγ is a transcription factor required for induction of the M2a macrophage phenotype by IL-4 or IL-13 ( 20 , 22 ), (rev. in 45 ). PPARγ forms heterodimers with Retinoid X Receptor (RXR), and their ligands are involved in the regulation of PPARγ/RXR heterodimer transcriptional function in the M2 gene expression program ( 46 ).…”

Artificial intelligence-rationalized balanced PPARα/γ dual agonism resets dysregulated macrophage processes in inflammatory bowel disease

“…Dual and balanced PPARα/γ agonism enhanced bacterial clearance with only a moderate induction of proinflammatory cytokines or ROS. Such a response ensures that the macrophage functions within a ‘goldilocks’ zone, mounting inflammation that is just sufficient for microbial clearance and immunity 80 . In our analysis, the only other PPARrelated gene within the IBD network, i.e., Pgc1a, and its role within the PPARα/γ axis suggests that the intricate network of forward feedback loops orchestrated by Pgc1a may be critical for achieving the critical balance between immunity and inflammation, which is a key outcome of the dual PPARα/γ agonists.…”

Peroxisome Proliferator-Activated Receptors and the Hallmarks of Cancer

“…However, non-thiazolidindione agonists of PPARγ failed to induce anti-inflammatory responses [ 512 ], and PPARγ-deficient embryonic stem cells could be differentiated into the monocytic lineage, suggesting PPARγ-independent effects of thiazolidindiones and 15d-PGJ2 on inflammation [ 513 , 514 ]. Nevertheless, PPARγ is important for defining the lineage of tissue-resident macrophages through transcriptional modulation in regulating the differentiation of pre-macrophages and alveolar macrophages, Kupffer cells, adipose-associated macrophages, and intestinal macrophages (reviewed in [ 27 ]); moreover, its activation primes primary monocytes for M2 differentiation, resulting in more pronounced anti-inflammatory activity in M1 macrophages [ 515 ]. In the setting of cancer, PPARγ activation was shown to reverse the MDSC and M2 macrophage-mediated suppression of the cytotoxic T lymphocyte (CTL) anti-tumor responses [ 516 ].…”

“…Until now, only PPARα agonists (e.g., fibrates) have been in clinical use for lipid lowering, the prevention of atherosclerosis, and cardiovascular disease [ 15 , 16 ], while PPARγ agonists (e.g., thiazolidinediones) lower glucose by increasing insulin sensitivity, mainly in skeletal muscle and adipose tissue [ 17 ]. In addition to these “classical” applications for the treatment of metabolism-related diseases and metabolic syndrome, PPARs might be involved in a variety of diseases [ 18 ] and PPAR modulators might become interesting candidates for neurodegenerative disorders [ 19 ], addiction [ 20 ], psychiatric disorders [ 21 , 22 ], hepatic and kidney diseases [ 12 , 23 , 24 , 25 ], and autoimmune and inflammatory diseases [ 16 , 26 , 27 , 28 , 29 ]. Importantly, PPARs are also critically involved in cancer.…”