Effects of Cathepsin S Inhibition in the Age-Related Dry Eye Phenotype

ABSTRACT: Purpose: Aged C57BL/6J (B6) mice have increased levels of cathepsin S, and aged cathepsin S (Ctss-/-) knockout mice are resistant to age-related dry eye. This study investigated the effects of cathepsin S inhibition on age-related dry eye disease. Methods: Female B6 mice aged 15.5 to 17 months were randomized to receive a medicated diet formulated by mixing the RO5461111 cathepsin S inhibitor or a standard diet for at least 12 weeks. Cornea mechanosensitivity was measured with a Cochet-Bonnet esthesiometer. Ocular draining lymph nodes and lacrimal glands (LGs) were excised and prepared for histology or assayed by flow cytometry to quantify infiltrating immune cells. The inflammatory foci (>50 cells) were counted under a 10× microscope lens and quantified using the focus score. Goblet cell density was investigated in periodic acid-Schiff stained sections. Ctss-/- mice were compared to age-matched wild-type mice. Results: Aged mice subjected to cathepsin S inhibition or Ctss-/- mice showed improved conjunctival goblet cell density and cornea mechanosensitivity. There was no change in total LG focus score in the diet or Ctss-/- mice, but there was a lower frequency of CD4+IFN-γ+ cell infiltration in the LGs. Furthermore, aged Ctss-/- LGs had an increase in T central memory, higher numbers of CD19+B220-, and fewer CD19+B220+ cells than wild-type LGs. Conclusions: Our results indicate that therapies aimed at decreasing cathepsin S can ameliorate age-related dry eye disease with a highly beneficial impact on the ocular surface. Further studies are needed to investigate the role of cathepsin S during aging.

• Autores: Trujillo Vargas, Claudia Milena; Galletti, Jeremias G.; Scholand, Kaitlin K.; Haap, Wolfgang; Santos Ferreira, Tiago; Ullmer, Christoph; Yu, Zhiyuan; de Paiva, Cintia S.
• Tipo de recurso: Article of investigation
• Fecha de publicación: 2023
• Institución: Universidad de Antioquia
• Repositorio: Repositorio UdeA
• Idioma: eng
• OAI Identifier: oai:bibliotecadigital.udea.edu.co:10495/39048
• Acceso en línea: https://hdl.handle.net/10495/39048
• Palabra clave: Modelos Animales de Enfermedad; Disease Models, Animal; Síndromes de Ojo Seco; Dry Eye Syndromes; Enfermedades del Aparato Lagrimal; Lacrimal Apparatus Diseases; Ratones Endogámicos C57BL; Mice, Inbred C57BL; Alcohol Polivinílico; Polyvinyl Alcohol; Lagrimas - metabolismo; Tears - metabolism; https://id.nlm.nih.gov/mesh/D015352; https://id.nlm.nih.gov/mesh/D008810; https://id.nlm.nih.gov/mesh/D004195; https://id.nlm.nih.gov/mesh/D007766; https://id.nlm.nih.gov/mesh/D011142; https://id.nlm.nih.gov/mesh/D013666
• Rights: openAccess
• License: https://creativecommons.org/licenses/by-nc-nd/4.0/