Antioxidant Function is Essential for Giant Cell Formation and Maintenance in Sarcoidosis Granulomas 2164

Abstract Description Multinucleated giant cells are hallmark features of sarcoidosis granulomas, yet their molecular characteristics remain poorly understood due to technical limitations of single-cell RNA sequencing. We employed an integrated approach combining histological analysis and spatial transcriptomics to decipher the unique gene expression patterns of giant cells in sarcoidosis patient samples. Using spatial transcriptome analysis, we discovered significant upregulation of phagocytosis and lipid metabolism-associated genes in multinucleated giant cells. Most notably, we identified elevated expression of thioredoxin and thioredoxin reductase, key mediators of cellular antioxidant defense. Immunohistochemical validation confirmed specific localization of thioredoxin reductase to multinucleated giant cells. To test the functional significance of these findings, we utilized an in vitro granuloma model. Treatment with thioredoxin reductase inhibitors effectively prevented both giant cell formation and granuloma development. These results demonstrate that antioxidant pathways are critical for giant cell maintenance and suggest that targeting redox mechanisms could represent a promising therapeutic strategy for sarcoidosis. This study provides the first comprehensive molecular characterization of sarcoidosis giant cells and establishes antioxidant function as an essential component of granuloma formation, offering new directions for therapeutic intervention in granulomatous diseases. Funding Sources This work was supported by the Japan Society for the Promotion of Science KAKENHI (20H05697 to KK; 23K07782 to SN), AMED-CREST (JP24gm1910006), AMED (JP23ek0109687), and the KOSE Cosmetology Research Foundation. Topic Categories Mucosal and Regional Immunology (MUC)