Cathepsin S is a novel target for age-related dry eye

Yu, Zhiyuan; Li, Jinmiao; Govindarajan, Gowthaman; Jahangir, Alam; Li, Dequan; Paiva, Cintia S. de

doi:10.1016/j.exer.2021.108895

Cited by 14 publications

(12 citation statements)

References 77 publications

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“… 26 , 27 The age-associated increase in inflammation might create a vicious cycle, as inflammatory cytokines like IFN-γ, TNF, and IL-1β are known to upregulate cathepsin S, 28 , 29 which in turn upregulates IL-1β and TNF (TNF is no longer named TNF-α 30 ). In line with this, cathepsin S increases with aging in the retina, brain, and lacrimal gland of mice, 17 , 31 , 32 and we have previously shown that aged tears have high levels of active cathepsin S. 33 …”

supporting

confidence: 66%

“…We previously reported that aged mice have increased cathepsin S activity in tears and Ctss −/− mice have diminished age-related corneal barrier disruption and do not lose goblet cells with age. 33 In this study, we subjected mice aged 15.5 to 17 months to a cathepsin S inhibition diet to investigate if cathepsin S blockade could be used to revert the age-related dry eye phenotype in mice. 10 , 44 Mice show signs of dry eye disease as early as 12 months.…”

Section: Resultsmentioning

confidence: 99%

“…Cathepsin S inhibitors have been developed and tested in many preclinical models of autoimmunity to decrease the generation of autoreactive T cells by interfering with MHC II presentation. 19 , 34 – 36 Because Sjögren syndrome and aged lacrimal glands share many similarities and activation of pathways related to immune activation, 10 and because our work showed that 1-year-old Ctss −/− mice have less severe dry eye phenotype than aged wild-type controls, 33 we hypothesized that a diet containing a cathepsin S inhibitor would also be beneficial during aging. The cathepsin S inhibitor RO5461111 was chosen since it is a selective inhibitor of cathepsin S. 34 …”

mentioning

confidence: 99%

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

Galletti

Scholand

Trujillo-Vargas

et al. 2023

Invest. Ophthalmol. Vis. Sci.

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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.

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confidence: 66%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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

Galletti

Scholand

Trujillo-Vargas

et al. 2023

Invest. Ophthalmol. Vis. Sci.

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“…In particular, for DED, the role of MMP-9 has been widely studied [ 19 ]. Even though the role of other proteases is less well established, there is evidence that serine and cysteine proteases also play a role in the immunity and inflammation of DED [ 37 , 38 ].…”

Section: Introductionmentioning

confidence: 99%

Proteases and Their Potential Role as Biomarkers and Drug Targets in Dry Eye Disease and Ocular Surface Dysfunction

Ramos-Llorca

Scarpellini

Augustyns

2022

IJMS

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Dry eye disease (DED) is a multifactorial disorder that leads to ocular discomfort, visual disturbance, and tear film instability. DED is accompanied by an increase in tear osmolarity and ocular surface inflammation. The diagnosis and treatment of DED still present significant challenges. Therefore, novel biomarkers and treatments are of great interest. Proteases are present in different tissues on the ocular surface. In a healthy eye, proteases are highly regulated. However, dysregulation occurs in various pathologies, including DED. With this review, we provide an overview of the implications of different families of proteases in the development and severity of DED, along with studies involving protease inhibitors as potential therapeutic tools. Even though further research is needed, this review aims to give suggestions for identifying novel biomarkers and developing new protease inhibitors.

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“… 34 , 35 We and others have used aged mice as a model of dry eye disease. As seen in dry eye disease, aged mice have (1) increased corneal permeability, 36 – 38 (2) conjunctival goblet cell loss, 37 , 39 , 40 (3) increased corneal irregularity, 41 (4) increased immune infiltration in the conjunctiva, 42 (5) meibomian gland disease, 43 – 48 (6) an altered tear immunoglobulin profile, 49 (7) altered tear cytokines, 40 , 50 , 51 and (8) increased immune infiltration in the lacrimal gland. 36 , 48 , 50 – 54 Corneal aging produces both structural and functional changes that can affect the ability of the organ to refract light, repair itself, and maintain its barrier function.…”

mentioning

confidence: 99%

Age-Related Differences in the Mouse Corneal Epithelial Transcriptome and Their Impact on Corneal Wound Healing

Abu-Romman,

Scholand,

Govindarajan

et al. 2024

Invest. Ophthalmol. Vis. Sci.

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Purpose Aging is a risk factor for dry eye. We sought to identify changes in the aged mouse corneal epithelial transcriptome and determine how age affects corneal sensitivity, re-epithelialization, and barrier reformation after corneal debridement. Methods Corneal epithelium of female C57BL/6J (B6) mice of different ages (2, 12, 18, and 24 months) was collected, RNA extracted, and bulk RNA sequencing performed. Cornea sensitivity was measured with an esthesiometer in 2- to 3-month-old, 12- to 13-month-old, 18- to 19-month-old, and 22- to 25-month-old female and male mice. The 2-month-old and 18-month-old female and male mice underwent unilateral corneal debridement using a blunt blade. Wound size and fluorescein staining were visualized and photographed at different time points, and a re-epithelialization rate curve was calculated. Results There were 157 differentially expressed genes in aged mice compared with young mice. Several pathways downregulated with age control cell migration, proteoglycan synthesis, and collagen trimerization, assembly, biosynthesis, and degradation. Male mice had decreased corneal sensitivity compared with female mice at 12 and 24 months of age. Aged mice, irrespective of sex, had delayed corneal re-epithelialization in the first 48 hours and worse corneal fluorescein staining intensity at day 14 than young mice. Conclusions Aged corneal epithelium has an altered transcriptome. Aged mice regardless of sex heal more slowly and displayed more signs of corneal epithelial defects after wounding than young mice. These results indicate that aging significantly alters the corneal epithelium and its ability to coordinate healing.

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Cathepsin S is a novel target for age-related dry eye

Cited by 14 publications

References 77 publications

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

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

Proteases and Their Potential Role as Biomarkers and Drug Targets in Dry Eye Disease and Ocular Surface Dysfunction

Age-Related Differences in the Mouse Corneal Epithelial Transcriptome and Their Impact on Corneal Wound Healing

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