Restoration of regulatory T cell function in dry eye disease by antagonizing substance P/neurokinin-1 receptor.

Abstract Substance P (SP) is a tachykinin neuropeptide, implicated in the pathogenesis of various inflammatory conditions, and a critical mediator in pain transmission. Recently, we demonstrated the role of SP in the pathogenesis of dry eye disease (DED) through its role in the maturation of antigen-presenting cells at the ocular surface following exposure to desiccating stress. However, the effect of SP on regulatory T cells (Tregs), which are functionally impaired in DED, remains unclear. The present study examined the phenotypic and functional changes in Tregs in response to SP in DED. The in vitro cultures of normal Tregs in the presence of SP led to a significant reduction in both Treg frequencies and their suppressive function, which was prevented by the addition of an SP receptor (neurokinin-1 receptor, NK-1R) antagonist. Furthermore, in vivo treatment with NK-1R antagonist in DED mice effectively restored Treg function, suppressed pathogenic Th17 response, and significantly ameliorated the disease. Our results demonstrate that a significant increase in the SP levels promotes Treg dysfunction in DED, and blockade of SP effectively restores Treg function and suppress DED severity.