Kurzfassung

Aim of this project is to study the role of specific G-protein-coupled receptors (GPCRs) in immune cells and endothelial cells in the context of neuroinflammation.
During the previous funding period we characterized the role of two recently deorphanized GPCRs, EBI2/GPR183 and HCA2/GPR109A, in the pathogenesis and therapy of multiple sclerosis (MS) and its mouse model, experimental autoimmune encephalomyelitis (EAE). We found that EBI2 expression is high both in murine and human TH17 cells, and...Aim of this project is to study the role of specific G-protein-coupled receptors (GPCRs) in immune cells and endothelial cells in the context of neuroinflammation.
During the previous funding period we characterized the role of two recently deorphanized GPCRs, EBI2/GPR183 and HCA2/GPR109A, in the pathogenesis and therapy of multiple sclerosis (MS) and its mouse model, experimental autoimmune encephalomyelitis (EAE). We found that EBI2 expression is high both in murine and human TH17 cells, and that it confers pathogenicity to myelin specific TH17 cells in an adoptive transfer model of EAE. Moreover, we found that the enzyme CH25H, which is important for production of the EBI2 ligand 7a,25-OHC, is highly upregulated in the course of EAE in the spinal cord, pointing for a role of 7a,25-OHC mediated CNS-transmigration of encephalitogenic T cells in EAE (Wanke et al., submitted). HCA2, in comparison, is not expressed on lymphoid cells, but on various myeloid cell types. We were able to show that dimethyl fumarate (DMF), an immunomodulatory drug recently approved for MS therapy, negatively regulates neutrophil migration and adhesion through HCA2, thereby contributing to the therapeutic effect of DMF (Chen et al., J Clin Invest 2014). To identify new GPCRs with yet unknown functions in neuroinflammation, we are currently performing a systematic single cell GPCR expression analysis in various immune cell populations. Aim of this study is to identify GPCRs that are expressed in small (but functionally relevant) immune cell subpopulations and activated endothelial cells.
In the upcoming funding period we will build on the results of our single cell-based analysis of GPCR expression in cell types implicated in neuroinflammation. We have already identified GPCRs that show specific expression patterns in subpopulations of naïve or spinal cord infiltrating CD4+ T cells, or regulatory T cells (Treg); we will further extend these studies to macrophages and resident populations such as endothelial cells or microglia. Focusing on those receptors that have not yet been implicated on neuroinflammation, we will employ in vitro and in vivo pharmacology as well as conditional knockout models to functionally characterize these GPCRs. We will also extend our single cell expression and pharmacological analysis to patient material (PBMC, CSF leukocytes) obtained within the CRC (Z2).» weiterlesen» einklappen