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

Abstract

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.