Linking metabolism to immunity through PPARγ

The nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) has been implicated in the function of immune cells, including dendritic cells. In this issue of Blood, Szatmari and colleagues report that the primary effect of PPARγ activation in developing human dendritic cells (DCs) is to regulate genes involved in lipid metabolism, and that the ability of this transcription factor to alter immune function is likely secondary to this metabolic reprogramming.

PPARs are nuclear receptors that regulate gene expression linked to lipid metabolism in a variety of cell types. All 3 isoforms (PPARα, PPARδ, and PPARγ) are activated by various native and oxidized fatty acids; however, the identities of the relevant endogenous activators in specific contexts are still unknown. The function of PPARγ in myeloid cells has been of particular interest in recent years following reports that this receptor is highly expressed in mature myeloid cells and may have anti-inflammatory effects.

DCs are professional antigen-presenting cells that bridge innate and adaptive immune responses. DCs capture antigens via phagocytosis and present them to T cells, thereby activating T cells and directing them toward specific effector pathways. PPARγ expression is highly up-regulated during DC differentiation and has been suggested to be an important modifier of DC function. Activation of PPARγ in DCs has been reported to enhance phagocytic capacity, to alter cytokine production, to enhance their capacity to activate NKT cells, and to contribute to the development of CD4⁺ T-cell anergy.^1-3  PPARγ is postulated to exert its biological effects through both positive actions on genes linked to lipid metabolism as well as negative effects on genes associated with inflammation. The relative importance of these transcriptional pathways for the maturation and function of DCs, however, has not been systematically explored.

In this issue of Blood, Szatmari and colleagues have analyzed developing human DCs to determine how genes involved in lipid metabolism and the immune response are linked by PPARγ. By performing extensive gene-expression profiling in PPARγ-activated human DCs, they identified more than 1000 transcripts that are regulated by this transcription factor. Remarkably, genes involved in lipid metabolism comprised the primary class of transcripts changed in early stages of DC maturation, while genes linked to immune responses were altered at later phases of maturation. The authors further report that human serum contains an as-yet-unidentified endogenous PPARγ activator or ligand precursor that modifies DC gene expression. Importantly, in addition to confirming their profiling results using real-time polymerase chain reaction (PCR), Szatmari and coworkers also documented that the effects of PPARγ ligands in their studies were receptor-dependent. Global analysis of gene expression in cells from human patients with dominant-negative PPARγ mutations revealed impaired responses in the PPARγ lipid metabolic program.

These observations support the intriguing hypothesis that primary changes in lipid metabolism in antigen-presenting cells are linked to the secondary modification of immune responses. Exactly how this crosstalk might be affected, however, remains to be determined. Interestingly, recent studies in macrophages have also pointed to a close link between cellular lipid metabolism and macrophage subtype specification.⁴  Together, these studies provide a solid base for future examination of the mechanistic connections between PPARγ-regulated genes involved in lipid metabolism and immune responses.