老化是一个复杂的生物过程，其特点是低度炎症，称为“炎性老化”。老化影响多个器官，包括眼睛和泪腺。肿瘤坏死因子（TNF）是一种多效应细胞因子，参与炎症反应、蛋白酶如半胱氨酸蛋白酶S的活化以及异位淋巴器官的形成。我们采用遗传和药物学方法，研究TNF在与年龄相关的干眼病中的作用，重点关注眼表面和泪腺的炎症反应。我们的结果显示，老龄泪腺中TNF的蛋白质和mRNA水平增加，伴随老龄小鼠泪液中TNF、IL1β、IL-18、CCL5、CXCL1、IL-2、IL-2受体α（CD25）、IFN-γ、IL-12p40、IL-17和IL-10蛋白增加。此外，在Tnf-/-小鼠中，与野生型小鼠相比，高尔基细胞损失和异位淋巴结构的发展减少，伴随着细胞因子产生的减少。在老龄小鼠早期（12-14个月龄）使用TNF抑制剂丹芬那塞滴眼液治疗八个连续周，与用药组相比，泪液中的细胞因子水平下降，高尔基细胞密度改善，并且泪腺的边缘区B细胞频率下降。我们的研究表明，在老化过程中调控TNF可能是治疗与年龄相关的干眼病的一种新策略。版权所有 © 2023. Elsevier Inc. 发表

Aging is a complex biological process that is characterized by low-grade inflammation, called inflammaging. Aging affects multiple organs including eye and lacrimal gland. Tumor necrosis factor (TNF) is a pleiotropic cytokine that participates in inflammation, activation of proteases such as cathepsin S, and formation of ectopic lymphoid organs. Using genetic and pharmacological approaches, we investigated the role of TNF in age-related dry eye disease, emphasizing the ocular surface and lacrimal gland inflammation. Our results show the increased protein and mRNA levels of TNF in aged lacrimal glands, accompanied by increased TNF, IL1β, IL-18, CCL5, CXCL1, IL-2, IL-2 receptor alpha (CD25), IFN-γ, IL-12p40, IL-17, and IL-10 proteins in tears of aged mice. Moreover, genetic loss of the Tnf-/- in mice decreased goblet cell loss and the development of ectopic lymphoid structures in the lacrimal gland compared to wild-type mice. This was accompanied by a decrease in cytokine production. Treatment of mice at an early stage of aging (12-14-month-old) with TNF inhibitor tanfanercept eye drops for eight consecutive weeks decreased cytokine levels in tears, improved goblet cell density, and decreased the marginal zone B cell frequency in the lacrimal gland compared to vehicle-treated animals. Our studies indicate that modulation of TNF during aging could be a novel strategy for age-related dry eye disease.Copyright © 2023. Published by Elsevier Inc.