1. TNF is a critical cytokine in age-related dry eye disease.
- Author
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Kelagere Y, Scholand KK, DeJong EN, Boyd AI, Yu Z, Astley RA, Callegan MC, Bowdish DM, Makarenkova HP, and de Paiva CS
- Subjects
- Animals, Mice, Cytokines metabolism, Tumor Necrosis Factor-alpha genetics, Tumor Necrosis Factor-alpha metabolism, Tumor Necrosis Factor-alpha therapeutic use, Tears metabolism, Inflammation metabolism, Disease Models, Animal, Dry Eye Syndromes metabolism, Lacrimal Apparatus metabolism
- Abstract
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 Elsevier Inc. All rights reserved.)- Published
- 2023
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