Laszlo Nagy's Research Focus
Dr. Nagy is a physician by training and a molecular and cell biologist with a long-standing research interest in the biology of gene-expression regulation, cellular differentiation, and their contribution to human diseases. The fundamental question he raises in his research is how lipid signaling regulates gene expression and how a changing extra- and intracellular lipid environment impacts the expression of the genome and contributes to changing cellular phenotypes. He uses the paradigm of nuclear hormone receptor activation/signaling and the contribution of this process to myeloid cell differentiation, function, and to diseases, involving these cells, such as atherosclerosis, tissue regeneration, metabolic, and various inflammatory disorders, as his model systems. He uses genome-wide and epigenomic approaches along with bioinformatics and data integration.
Laszlo Nagy's Research Report
Cells of the immune system respond to a changing environment by adjusting their phenotype and immune functions. Signals from pathogens, tissue factors, and other immune cells are involved in defining the immune phenotype of these cell types. Some of these signals are in the form of lipids, which contribute to fine-tuning the immune responses of cells such as macrophages and dendritic cells. How changes in extra- and intracellular lipid environments affect immune cell function and the mechanisms responsible for bringing about these changes are, however, poorly understood. We have been interested in identifying such mechanisms in macrophages and dendritic cells, two important cell types derived from the myeloid lineage that participate in the immune response and that are implicated in various inflammatory conditions such as autoimmunity and chronic inflammation.
Candidates for lipid-metabolite sensors of inflammatory status are members of the family of the peroxisome proliferator-activated receptors (PPARs), which are expressed in many immune cells. PPARs are members of the nuclear hormone receptor superfamily of transcription factors. Their activity is regulated by lipophilic compounds. PPARs form heterodimers with the retinoid X receptor (RXR) and regulate transcription of their target genes and gene networks. PPARγ was initially linked to adipocyte (fat cell) differentiation, but we now know that it also regulates genes responsible for lipid uptake, accumulation, and storage of lipids in those cells. Moreover, synthetic activators of this receptor have been used to treat type 2 diabetes. This receptor is therefore a well-established and thoroughly characterized component of lipid metabolism and a drug target for metabolic diseases. It was also reported that PPARγ is expressed in cells of monocyte origin such as macrophages and that it modulates the function of these cells. PPARγ appears to be part of a network of transcription factors coordinately regulating lipid uptake and cholesterol efflux in macrophages by transcriptionally regulating the scavenger receptor CD36 and the oxysterol receptor LXRα (liver X receptor α). PPARγ ligands also have anti-inflammatory effects that are achieved by blocking the induction of several proinflammatory cytokines by a poorly understood trans-repressional mechanism.
Recently, several observations suggested that, besides monocyte-derived macrophages, dendritic cells, a distinct myeloid lineage, also express PPARγ at high levels. Dendritic cells are professional antigen-presenting cells with a unique capacity to prime naive T cells. After detecting microbial products or pro-inflammatory cytokines, immature dendritic cells transform into mature dendritic cells, which exhibit an exceptional capacity for T cell activation. This activation takes place in vivo in lymphoid tissues such as the lymph nodes and tonsils. Depending on the antigen, dendritic cells are able to initiate either an immune response or tolerance. The molecular details of this “decision-making” process are not well understood.
By analyzing the role of PPARγ in dendritic cells using molecular, genomic, and pharmacologic approaches, we identified genes and gene networks regulated by this receptor. Activation of the receptor leads to dendritic cell lineage specification and regulation of lipid antigen presentation. We found that CD1 glycoproteins, a class of molecules responsible for the presentation of self and foreign lipids, are coordinately regulated by PPARγ activation. Enhanced expression of one of these molecules, CD1d, is coupled to selective induction of invariant natural-killer T cells (iNKT), a subset of T lymphocytes that are present at low levels in lymphocyte populations and whose absence enhances autoimmunity in animal models. iNKT cells are also capable of producing high levels of cytokines such as interferon-γ and interleukin-4. Our results suggest that the lipid-activated transcription factor PPARγ orchestrates a transcriptional response leading to the development of a dendritic cell subtype with increased internalizing capacity, efficient lipid presentation, and augmented potential to activate iNKT cells.
In an attempt to identify the molecular mechanisms underlying PPARγ action, we have demonstrated that PPARγ turns on intracellular retinoic acid synthesis from vitamin A by inducing the expression of retinol- and retinal-metabolizing enzymes such as retinol dehydrogenase 10 and retinaldehyde dehydrogenase 2. Increased expression of these enzymes leads to intracellular generation of all-trans-retinoic acid (ATRA) from retinol (vitamin A). ATRA regulates gene expression by activating the retinoic acid receptor. These findings show that regulation of retinoid metabolism and signaling is part of PPARγ-controlled events in these cells. This mechanism allows dendritic cells to respond to altered lipid homeostasis by changing gene expression and immunophenotype.
In summary, our findings provide insights into the regulatory logic and inter-relatedness of lipid (fatty acid, cholesterol, and retinoid) signaling in cells of the immune system. The data show that lipid processing and metabolism are coupled to immune responses via the activity of nuclear hormone receptors. They further show that, by regulating lipid metabolism, a cell is able to switch its immune phenotype by using transcriptional mechanisms and that the lipid environment has an important impact on immune cell function. These pathways might also be amenable to therapeutic intervention in inflammatory and immune diseases.
Laszlo Nagy's Bio
Dr. Nagy is a physician-scientist and a cell and molecular biologist. He obtained an M.D. and subsequently a Ph.D. from the University of Debrecen, Hungary. He carried out two post-doctoral training periods at the University of Texas-Houston and later at the Salk Institute in San Diego.