RHEUMATOID ARTHRITIS SYNOVIAL MICROENVIRONMENT INDUCES METABOLIC AND FUNCTIONAL ADAPTATIONS IN DENDRITIC CELLS
Rheumatoid Arthritis (RA) is a chronic autoimmune disease which causes degradation of cartilage and bone. It is well appreciated that the pathogenic hallmark of RA is the mass influx of inflammatory cells into the joint. However, the role dendritic cells (DC) may play in this inflammatory milieu is still relatively unexplored. Moreover, the contribution this unique synovial microenvironment has on DC function and maturation is still unknown. Using monocyte-derived DC (MoDC), we established an in vitro model to recapitulate the synovial microenvironment to explore DC maturation. MoDC treated with conditioned media from ex vivo synovial tissue biopsy cultures (ECM) have increased expression of proinflammatory cytokines, chemokines and adhesion molecules. ECM treated DC have increased expression of CD83 and CCR7 and decreased expression of CCR5 and phagocytic capacity, suggestive of heightened DC maturation. ECM induced maturation is concomitant with altered cellular bioenergetics, whereby increased expression of glycolytic genes and increased glucose uptake are observed in ECM treated DC. Collectively, this results in a metabolic shift in DC metabolism in favor of glycolysis. These adaptations are in-part mediated via STAT3 as demonstrated by decreased expression of proinflammatory cytokines and glycolytic genes in ECM treated DC in response to STAT3 inhibition. Finally, to translate this data to a more in vivo clinically relevant setting, we interrogated a previously published synovial DC dataset and identified enhanced expression of glycolytic genes in synovial DC compared to DC in circulation. Collectively, our data suggests that the synovial microenvironment in RA contributes to DC maturation and metabolic reprogramming. Overall design: 9 samples