OP0192 S100 Proteins in Dendritic Cells Regulate Inflammatory Processes

BackgroundS100A8 and S100A9, also known as myeloid-related protein-8 (MRP8) and MRP14, are widely used as biomarkers of disease activity in juvenile idiopathic arthritis. On a molecular level these proteins function as damage-associated molecular pattern molecules (DAMPs), which amplify inflammation via Toll-like receptor-4 (TLR-4) activation. Released from activated phagocytes or necrotic cells the physiologically relevant S100A8/A9 heterodimers stimulate surrounding cells in order to promote pro-inflammatory processes in innate immunity. Adaptive immunity is believed to be enhanced by these molecules via activation of dendritic cells (DCs). Interestingly, recent studies show an additional regulatory effect of S100 proteins on DCs upon prolonged exposure (Petersen et al. EMBO-J 2013).ObjectivesThe aim of this study is to decipher the S100 protein dependent molecular mechanisms in dendritic cells which enforce aggravation or attenuation of inflammation.MethodsHuman monocyte derived or murine bone marrow derived DCs are differentiated with or without exposure to S100A8 for six days prior to activation with LPS. After characterization and determination of the activation status using flow cytometry, the ability of these cells to induce T-cell proliferation is investigated in an autologous, antigen-specific or allogenic fashion. To identify the molecular mechanisms leading to the observed phenotype the mRNA expression of human DCs in various stages of differentiation was screened by genome-wide gene expression arrays.ResultsIn a model of allergic contact dermatitis S100A9 deficient mice developed elevated inflammatory responses compared to wild type mice. We could demonstrate that prolonged exposure of myeloid progenitor cells to S100 proteins blocks DC differentiation and antigen presentation resulting in a reduced OT1 and OT2 T-cell response. Human S100A8/A9 shows a similar regulatory impact on monocyte-derived DCs (moDCs), since early DC differentiation and subsequent antigen-presentation is inhibited by S100A8 as well, leading to altered T-cell responses associated with decreased proliferation and enhanced IL-10 secretion. Gene expression analysis of developing DCs indicates vast changes in prominent immune modulatory pathways like JAK/STAT, NOD, RIG-I and TLR signalling. In addition, cell adhesion and antigen presentation seems to be affected by metabolic changes (e.g. PPAR-γ regulated fatty acid biosynthesis) as well as surface expression of antigen pres