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

Jeremias G Galletti1,2, Kaitlin K Scholand1,3, Claudia M Trujillo-Vargas1,4

  • 1Department of Ophthalmology, Baylor College of Medicine, Houston, Texas, United States.

Investigative Ophthalmology & Visual Science
|August 4, 2023
PubMed
Abstract

Insights

Inhibiting cathepsin S (Ctss) in aged mice improved dry eye symptoms, including ocular surface health and corneal sensitivity. This suggests Ctss-targeted therapies may effectively treat age-related dry eye disease.

Area of Science:

  • Ophthalmology
  • Immunology
  • Aging Research

Background:

  • Aged C57BL/6J mice exhibit elevated cathepsin S (Ctss) levels.
  • Aged Ctss knockout mice demonstrate resistance to age-related dry eye.
  • Cathepsin S plays a role in the pathogenesis of age-related dry eye disease.

Purpose of the Study:

  • To investigate the therapeutic potential of cathepsin S inhibition in mitigating age-related dry eye.
  • To evaluate the impact of Ctss inhibition on ocular surface parameters and immune cell infiltration in aged mice.

Main Methods:

  • Female C57BL/6J mice (15.5-17 months old) received a diet with a Ctss inhibitor (RO5461111) or a standard diet for 12 weeks.
  • Corneal sensitivity was assessed using a Cochet-Bonnet esthesiometer.
  • Lacrimal glands and ocular draining lymph nodes were analyzed for immune cell populations and inflammatory foci via histology and flow cytometry.
  • Ctss knockout mice were compared to age-matched wild-type controls.

Main Results:

  • Cathepsin S inhibition and Ctss deficiency improved conjunctival goblet cell density and corneal mechanosensitivity in aged mice.
  • While overall lacrimal gland inflammation scores did not change, there was reduced infiltration of CD4+IFN-γ+ T cells in the lacrimal glands of treated and knockout mice.
  • Aged Ctss knockout lacrimal glands showed an increase in T central memory cells and altered B cell populations (more CD19+B220- and fewer CD19+B220+ cells) compared to wild-type.

Conclusions:

  • Therapies targeting cathepsin S effectively ameliorate age-related dry eye.
  • Decreasing cathepsin S levels positively impacts the ocular surface and corneal sensitivity.
  • Further research is warranted to fully elucidate the role of cathepsin S in the aging process and dry eye development.

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