Ets1 suppresses atopic dermatitis by suppressing pathogenic T cell responses

Abstract
Atopic dermatitis (AD) is a complex inflammatory skin disorder driven by both adaptive and innate immune cells. Among these, CD4+ T helper (Th) cells play a significant role in the development of AD. While the involvement of Th2 cells in AD has been well-established, Th17 and Th22 cells are also recognized as contributing factors in the disease. Despite this, the precise molecular mechanisms behind the immune responses in AD remain poorly understood. In this study, we explored how a defect in the AD susceptibility gene Ets1 contributes to AD pathogenesis in both humans and mice, as well as its potential impact on disease severity by identifying Ets1 target genes and binding partners. Consistent with lower ETS1 levels observed in patients with severe AD and in an experimental AD-like skin inflammation model, mice with T cell-specific Ets1 deletion (Ets1ΔdLck) developed more severe AD-like symptoms, accompanied by heightened pathogenic Th cell responses. The loss of Ets1 in T cells led to an increase in gp130 expression, which in turn activated the IL-6 signaling pathway through gp130, exacerbating AD symptoms. Treatment with the selective gp130 inhibitor SC144 alleviated disease progression by reducing pathogenic Th cell activity. Our findings highlight the protective role of Ets1 in limiting harmful Th cell responses and suggest that targeting this pathway may offer a potential therapeutic strategy for AD.