Balance between Estrogens and Proinflammatory Cytokines Regulates Chemokine Production Involved in Thymic Germinal Center Formation

Abstract

Abstract The early-onset form of Myasthenia Gravis (MG) is prevalent in women and associates with ectopic germinal centers (GCs) development and inflammation in the thymus. we aimed to investigate the contribution of estrogens in the molecular processes involved in thymic GCs formation. We examined expression of genes involved in anti-acetylcholine receptor (AChR) response in MG, MHC class II and α-AChR subunit as well as chemokines involved in GC development (CXCL13, CCL21and CXCL12). In resting conditions, estrogens have strong regulatory effects on thymic epithelial cells (TECs), inducing a decreased protein expression of the above molecules. In knockout mouse models for estrogen receptor or aromatase, we observed that perturbation in estrogen transduction pathway altered MHC Class II, α-AChR, and CXCL13 expression. However, in inflammatory conditions, estrogen effects were partially overwhelmed by pro-inflammatory cytokines. Interestingly, estrogens were able to control production of type I interferon and therefore play dual roles during inflammatory events. In conclusion, we showed that estrogens inhibited expression of α-AChR and HLA-DR in TECs, suggesting that estrogens may alter the tolerization process and favor environment for an autoimmune response. By contrast, under inflammatory conditions, estrogen effects depend upon strength of the partner molecules with which it is confronted to.