Substance P regulates memory Th17 cell generation and maintenance in chronic dry eye disease

作者：Shudan Wang, Amirreza Naderi, Francesca Kahale, Gustavo Ortiz, Katayoon Forouzanfar, Yihe Chen, Reza Dana · 发表于：Journal of Leukocyte Biology · 年份：2024 · DOI：10.1093/jleuko/qiae142 · 被引用次数：13 · 研究领域：Neuropeptides and Animal Physiology、Ocular Surface and Contact Lens、Chemokine receptors and signaling

Substance P is a neuropeptide expressed by nerves and an array of cells that serves as a critical mediator of neuroinflammation. Our recent work has demonstrated that blocking the preferred receptor for substance P, neurokinin 1 receptor, effectively suppresses the induction of acute dry eye disease by preserving regulatory T-cell function, while inhibiting antigen-presenting cell maturation and subsequent generation of effector Th17 cells. Clinically, dry eye disease is a chronic disorder characterized by sustained ocular surface inflammation, which is mediated by long-lived memory Th17 cells demonstrated in our well-established chronic dry eye disease model. The present study aimed to further understand the function of substance P in the chronic phase of dry eye disease and its role in regulating the underlying pathogenic memory Th17. In vitro culture of effector T cells isolated from acute dry eye disease with substance P led to an enhanced conversion of effector Th17 to memory Th17, while culturing memory T cells isolated from chronic dry eye disease with substance P effectively preserved the memory Th17 cells. In contrast, the addition of a neurokinin 1 receptor antagonist in the cultures abolished the substance P-mediated effects. Furthermore, in vivo treatment with the neurokinin 1 receptor antagonist during the resolution phase of acute dry eye disease significantly suppressed memory Th17 generation, and treatment in the chronic phase of dry eye disease disrupted the ...