The aryl hydrocarbon receptor affects the inflammatory response of bone marrow mesenchymal stem cell via the hippo-YAP pathway to exacerbate systemic lupus erythematosus

The impaired immune regulation of bone marrow mesenchymal stem cells (BM-MSCs) disrupts T-cell homeostasis and alters the immunological environment in individuals with systemic lupus erythematosus (SLE). However, the specific molecular mechanisms underlying the defective immune functions of BM-MSCs in patients with SLE remain unclear. Here, we report that BM-MSCs derived from MRL/lpr mice exhibit a diminished proliferative capacity, elevated levels of Aryl Hydrocarbon Receptor (AhR) and increased levels of secreted proinflammatory cytokines, including IL-1β, IL-6, and TNF-α. These BM-MSCs can increase splenocyte proliferation and upregulate the expression of retinoic acid receptor-related Orphan Receptor gamma t (RORγt) in EL4 cells, which constitute a murine T-cell lymphoblastic leukemia cell line. Furthermore, MRL/lpr mice treated with FICZ (an AhR agonist) displayed splenomegaly and exacerbated renal pathology, alongside increased levels of AhR, and inflammatory cytokines. Notably, BM-MSCs isolated from FICZ-treated mice also facilitated splenocyte proliferation and increased the RORγt level in EL4 cells during coculture. Similar effects were observed when BM-MSCs were exposed to FICZ in vitro, but these effects were reversed by the administration of CH223191 (an AhR antagonist). Additionally, the expression of Yes-associated protein (YAP) was significantly increased in both MRL/lpr mice and FICZ-treated BM-MSCs. Importantly, verteporfin (a Hippo-YAP inhibitor) attenuated the elevated RORγt levels in EL4 cells and the increased splenocyte proliferation. This study advances our understanding of SLE pathogenesis by pinpointing AhR as a pivotal modulator of the inflammatory response of BM-MSCs through the Hippo-YAP pathway in individuals with SLE. This novel insight not only enriches the current knowledge of SLE mechanisms but also highlights new potential therapeutic targets for SLE.