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Peroxisome proliferator-activated receptor gamma in inflammation

Final Report Summary - PPARS (Peroxisome proliferator-activated receptor gamma in inflammation)

Project objectives

Peroxisome proliferators activated receptor gamma (PPARg) is a key regulator of lipid and carbohydrate metabolism. The fact that PPARg agonists are the main class of drugs in human medicine with a proven mechanistic effect on insulin resistance lends PPARg a profoundly important role in the treatment of type II diabetes. PPARg has also been recognised to be a regulator of immunity, partly due to its effects in immune cells. We aimed to map the functions of PPARg in immune cells.

Progress toward objectives

Specific Aim 1: the in-vivo role of PPARg signalling in the innate and adaptive immune system.

(A) Our laboratory has earlier reported that PPARgamma activation in monocyte derived dendritic cells (DCs) led to an enhanced capacity of these DCs to trigger autologous invariant natural killer T (iNKT) cell expansion. iNKT cells are immune cells that have the unique capacity to enhance either Th1 or Th2 type immunity. We have previously demonstrated that PPARg modulated iNKT expansion was partly due to an increased cell surface expression of CD1d molecules on DCs. We aimed to identify alternative mechanisms by which PPARg activated DCs could lead to iNKT expansion. We found that PPARg activation in DCs gave rise to an enhanced expression cathepsinD, a lysosomal protease. We demonstrated that PPARg regulated cathepsinD was required for the enhanced iNKT expansion. Our results suggest that PPARg plays a more profound role in iNKT immunity than previously anticipated.

(B) Parallel to the iNKT studies, we have started a fresh investigation in the PPARg regulation in DCs. We have earlier described that PPARg is expressed and transcriptionally active in human DCs. We have also observed an intriguing finding that addition of human serum to culture medium is able to activate PPARg in DCs. This suggests the presence of a hitherto unidentified endogenous present in human serum. We have found that donors serum samples contain variable amount of the putative ligand, and very importantly, the amount is characteristic to the donor and ligand-like activity of donors show little variation in time,. This raises the intriguing question if donors with low/high PPARg ligand-like activity have different predisposition to develop metabolic disease. We set out to collect a large set of serum samples from donors and once the sample collection is finished we would analyse the serum samples and their correlation with clinical parameters.

(C) We also aimed to reveal further functions of PPARg in macrophages/dendritic cells. We have pursuing a genetic approach with the help of murine inducible PPARg knock-out models. We generated macrophage and dendritic cell specific PPARg knock-out mouse strains. We pursue two approaches in two collaborations (A. Toxin generated muscle regeneration in collaboration with Benedicte Chazaud, Inserm, France. B. Immunity against parasitic infections in collaborations with Judith Allen, University of Edinburgh, United Kingdom). The preliminary experiments from the muscle regeneration experiments suggested that PPARg has a role in regulating muscle regeneration. An active collaboration has been set up to ascertain the role of PPARg. Dendritic cell specific retinoid X receptor (RXR) knock-out (the heterodimeric partner of many nuclear receptors, including PPARg) will also be generated to study the function of nuclear receptor signaling in DCs (CD11cCre-PPARG, and CD11c-RXRa). These strains have been recently generated and would be used in the future.

Specific aim 2: microRNA mediated transcriptional regulation

We extensively use human DCs as a model system to investigate transcriptional regulation. One aspect of this differentiation is the upregulation of short regulatory RNA molecules (miRNA). These regulatory RNAs have a previously unsuspected role in the fine-tuning of gene expression and cellular functions. We mapped the Interleukin 4 (IL4) dependent regulation of miRNAs in DCs and the study in the role of these miRNAs is under way.

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