Therapeutic effect of IL-11 inhibition on the pathogenesis of thyroid eye disease

Abstract

Thyroid eye disease (TED), a major extrathyroidal manifestation of Graves&apos; disease, is driven by the underlying autoimmune responses. This study aimed to elucidate the pathological role of IL-11 in TED and evaluate the therapeutic potential of LASN01, a potent, fully human antibody that targets IL-11 receptor alpha (IL-11R alpha). IL-11 (P < 0.001) and IL-11R alpha (P = 0.003) mRNA were significantly elevated in TED orbital tissues (n = 15) compared to normal controls (n = 15) by quantitative real-time polymerase chain reaction (RT-qPCR). IL-11 expressions in both TED and normal orbital fibroblasts (OFs) were upregulated after treatment with either transforming growth factor-beta (TGF-beta) or insulin-like growth factor 1 (IGF-1). Furthermore, IL-11 exerted a synergistic stimulatory effect on hyaluronan production in TED OFs when combined with either TGF-beta (3.21-fold, P < 0.001) or IGF-1 (2.83-fold, P < 0.001). Notably, the combination of IL-11 and TGF-beta induced greater procollagen production (6.17-fold, P < 0.001). Blocking IL-11R with LASN01 effectively reduced both hyaluronan (94% reduction, P < 0.001) and procollagen production (36% reduction, P = 0.002) in ELISA under various stimulation conditions. Finally, Western blot analysis showed that LASN01 blocked STAT3 and ERK phosphorylation in TED OFs, which are known as downstream effectors of IL-11 signaling. This study systematically analyzed how IGF-1 and TGF-beta promote IL-11 expression in OFs and examined the downstream effects of IL-11 on hyaluronan and procollagen production, highlighting the central role of IL-11 in TED-associated tissue expansion and fibrosis. The inhibitory effects of LASN01 on hyaluronan and procollagen production suggest that targeting IL-11R could represent an effective therapeutic option for TED, providing a foundation for future clinical applications.