TNF is a critical cytokine in age-related dry eye disease

Kelagere, Yashaswini; Scholand, Kaitlin K.; DeJong, Erica N.; Boyd, Andrea I.; Yu, Zhiyuan; Astley, Roger A.; Callegan, Michelle C.; Bowdish, Dawn ME.; Makarenkova, Helen P.; de Paiva, Cintia S.

doi:10.1016/j.jtos.2023.08.004

Cited by 9 publications

(3 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We found a correlation between tear CXCL1 concentration and severity of ocular irritation using data from our published survey of tear inflammatory mediators in SS (Figure 5B) (27). We have also found an increase in CXCL1 in the tears of aged mice that develop dry eye (Figure 5C) (28). Because CXCL1 is recognized to be a nociceptor sensitizer involved in chronic pain and TRPV1 activator (30,31) we evaluated if topical application of CXCL1 to the ocular surface heightened the pain response to topically applied TRPV1 (hypertonic saline) and TRPM8 (menthol) agonists (32)(33)(34)(35).…”

Section: Cxcl1 Is a Neurosensitizing Chemokine In Dry Eyesupporting

confidence: 59%

Single cell analysis of short-term dry eye induced changes in cornea immune cell populations

Alam,

Yaman,

Silva

et al. 2024

Front. Med.

Self Cite

View full text Add to dashboard Cite

BackgroundDry eye causes corneal inflammation, epitheliopathy and sensorineural changes. This study evaluates the hypothesis that dry eye alters the percentages and transcriptional profiles of immune cell populations in the cornea.MethodsDesiccating stress (DS) induced dry eye was created by pharmacologic suppression of tear secretion and exposure to drafty low humidity environment. Expression profiling of corneal immune cells was performed by single-cell RNA sequencing (scRNA-seq). Cell differentiation trajectories and cell fate were modeled through RNA velocity analysis. Confocal microscopy was used to immunodetect corneal immune cells. Irritation response to topical neurostimulants was assessed.ResultsTwelve corneal immune cell populations based on their transcriptional profiles were identified at baseline and consist of monocytes, resident (rMP) and MMP12/13 high macrophages, dendritic cells (cDC2), neutrophils, mast cells, pre T/B cells, and innate (γDT, ILC2, NK) and conventional T and B lymphocytes. T cells and resident macrophages (rMP) were the largest populations in the normal cornea comprising 18.6 and 18.2 percent, respectively. rMP increased to 55.2% of cells after 5 days of DS. Significant changes in expression of 1,365 genes (adj p < 0.0001) were noted in rMP with increases in cytokines and chemokines (Tnf, Cxcl1, Ccl12, Il1rn), inflammatory markers (Vcam, Adam17, Junb), the TAM receptor (Mertk), and decreases in complement and MHCII genes. A differentiation trajectory from monocytes to terminal state rMP was found. Phagocytosis, C-type lectin receptor signaling, NF-kappa B signaling and Toll-like receptor signaling were among the pathways with enhanced activity in these cells. The percentage of MRC1+ rMPs increased in the cornea and they were observed in the basal epithelium adjacent to epithelial nerve plexus. Concentration of the chemokine CXCL1 increased in the cornea and it heightened irritation/pain responses to topically applied hypertonic saline.ConclusionThese findings indicate that DS recruits monocytes that differentiate to macrophages with increased expression of inflammation associated genes. The proximity of these macrophages to cornea nerves and their expression of neurosensitizers suggests they contribute to the corneal sensorineural changes in dry eye.

show abstract

Section: Cxcl1 Is a Neurosensitizing Chemokine In Dry Eyesupporting

confidence: 59%

Single cell analysis of short-term dry eye induced changes in cornea immune cell populations

Alam,

Yaman,

Silva

et al. 2024

Front. Med.

Self Cite

View full text Add to dashboard Cite

show abstract

“…Tanfanercept is a topical solution made of a modified TNF receptor 1 (TNFR1), specifically from the TNFα binding fragment, that is able to block TNFα and its activity [ 53 ]. As previously mentioned, TNFα is a cytokine that plays a central role mediating the inflammatory cascade that contributes to the pathogenesis of multiple diseases, including DED, which suggest its downregulation as a potential treatment [ 54 ]. In a mouse model of DED (induced by subcutaneous injections of scopolamine hydrobromide and a controlled environmental chamber), topical tanfanercept suppressed inflammatory cytokines in corneal and lacrimal gland samples, in addition to improving goblet cell counts and corneal erosion scores [ 53 ].…”

Section: Dry Eye Disease Sourcesmentioning

confidence: 99%

Recent United States Developments in the Pharmacological Treatment of Dry Eye Disease

Valdés-Arias,

Locatelli,

Sepulveda-Beltran

et al. 2024

Drugs

View full text Add to dashboard Cite

Dry eye disease (DED) can arise from a variety of factors, including inflammation, meibomian gland dysfunction (MGD), and neurosensory abnormalities. Individuals with DED may exhibit a range of clinical signs, including tear instability, reduced tear production, and epithelial disruption, that are driven by different pathophysiological contributors. Those affected often report a spectrum of pain and visual symptoms that can impact physical and mental aspects of health, placing an overall burden on an individual’s well-being. This cumulative impact of DED on an individual’s activities and on society underscores the importance of finding diverse and effective management strategies. Such management strategies necessitate an understanding of the underlying pathophysiological mechanisms that contribute to DED in the individual patient. Presently, the majority of approved therapies for DED address T cell-mediated inflammation, with their tolerability and effectiveness varying across different studies. However, there is an emergence of treatments that target additional aspects of the disease, including novel inflammatory pathways, abnormalities of the eyelid margin, and neuronal function. These developments may allow for a more nuanced and precise management strategy for DED. This review highlights the recent pharmacological advancements in DED therapy in the United States. It discusses the mechanisms of action of these new treatments, presents key findings from clinical trials, discusses their current stage of development, and explores their potential applicability to different sub-types of DED. By providing a comprehensive overview of products in development, this review aims to contribute valuable insights to the ongoing efforts in enhancing the therapeutic options available to individuals suffering from DED.

show abstract

“… 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.

Self Cite

View full text Add to dashboard Cite

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.

show abstract

TNF is a critical cytokine in age-related dry eye disease

Cited by 9 publications

References 58 publications

Single cell analysis of short-term dry eye induced changes in cornea immune cell populations

Single cell analysis of short-term dry eye induced changes in cornea immune cell populations

Recent United States Developments in the Pharmacological Treatment of Dry Eye Disease

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

Contact Info

Product

Resources

About