Diabetic retinopathy (DR) is a leading cause of blindness in working-age adults and remains an important public health issue worldwide. Here we demonstrate that the expression of stimulator of interferon genes (STING) is increased in patients with DR and animal models of diabetic eye disease. STING has been previously shown to regulate cell senescence and inflammation, key contributors to the development and progression of DR. To investigate the mechanism whereby STING contributes to the pathogenesis of DR, diabetes was induced in STING -KO mice and STING ^GT (loss-of-function mutation) mice, and molecular alterations and pathological changes in the retina were characterized. We report that retinal endothelial cell senescence, inflammation, and capillary degeneration were all inhibited in STING -KO diabetic mice; these observations were independently corroborated in STING ^GT mice. These protective effects resulted from the reduction in TBK1, IRF3, and NF-κB phosphorylation in the absence of STING. Collectively, our results suggest that targeting STING may be an effective therapy for the early prevention and treatment of DR.

Purpose: The purpose of this study was to study the status and association among tear-soluble factors, corneal dendritic cell density, vitamin D, and signs and symptoms in dry eye disease (DED). Methods: A total of 33 control subjects and 47 evaporative dry eye patients were included in the study. DED diagnosis and classification was based on the 2017 Report of the Tear Film & Ocular Surface Society International Dry Eye Workshop (TFOS DEWS II). DED workup, including tear film break-up time (TBUT), Schirmer's test I (STI), corneal and conjunctival staining, ocular surface disease index (OSDI) scoring, and in vivo confocal microscopy (to assess corneal dendritic cell density [cDCD] and subbasal nerve plexus [SBNP] features) was performed in the study subjects. Tear fluid using Schirmer's strip and serum were collected from the subjects. Multiplex ELISA or single analyte ELISA was performed to measure 34 tear-soluble factors levels including vitamin D. Results: Significantly higher OSDI discomfort score, lower TBUT, and lower STI were observed in DED patients. cDCD was significantly higher in DED patients. No significant difference was observed in SBNP features. Tear fluid IL-1β, IL-17A, MMP9, MMP10, MMP9/TIMP ratio, and VEGF-B were significantly higher in DED patients. Significantly lower tear fluid IL-2, IP-10, NPY, VEGF-A, and vitamin D was observed in DED patients. These dysregulated tear factors showed significant associations with DED signs and symptoms. Conclusions: Altered tear fluid soluble factors with potential to modulate nociception exhibited a distinct association with ocular surface discomfort status, TBUT, STI, and cDCD. This implies a functional relationship between the various tear-soluble factors and dry eye pathogenesis, indicating new molecular targets for designing targeted therapies.

Inflammatory factors have been considered to contribute to keratoconus (KC) pathogenesis. This study aims to determine the immune cells subsets and soluble inflammatory factor profile on the ocular surface of KC patients. 32 KC subjects (51 eyes) across different grades of severity and 15 healthy controls (23 eyes) were included in the study. Keratometry and pachymetry measurements were recorded. Ocular surface immune cells (collected by ocular surface wash) immunophenotyped using flow cytometry include leukocytes, neutrophils, macrophages, natural killer (NK) cells, pan-T cells, gamma delta T (γδT) cells and NKT cells. Tear fluid collected using Schirmer’s strip was used to measure 50 soluble factors by multiplex ELISA. Proportions of activated neutrophils, NK cells and γδT cells were significantly increased in KC patients. Significantly higher levels of tear fluid IL-1β, IL-6, LIF, IL-17A, TNFα, IFNα/β/γ, EPO, TGFβ1, PDGF-BB, sVCAM, sL-selectin, granzyme-B, perforin, MMP2, sFasL and IgE, along with significantly lower levels of IL-1α and IL-9 were observed in KC patients. Alterations observed in few of the immuno-inflammatory parameters correlated with grades of disease, allergy, eye rubbing and keratometry or pachymetry measurements. The observation implies a distinct immuno-inflammatory component in KC pathogenesis and its potential as an additional therapeutic target in KC management.

Keratoconus (KC) is a corneal ectatic condition characterized by focal structural changes, resulting in progressive thinning, biomechanical weakening, and steeping of the cornea that can lead to worsening visual acuity due to irregular astigmatism and corneal scarring in more advanced cases. It is a relatively common ectatic disease of the cornea predominantly affecting the younger population. Despite its worldwide prevalence, its incidence is rather varied with a higher incidence among the Middle Eastern and South Asian population. Dysregulated corneal extracellular matrix remodeling underlies KC pathogenesis. However, a lack of absolute clarity regarding the factors that initiate and drive progression poses a significant challenge in its prevention and management. KC is a complex multifactorial disease as it is associated with a wide variety of etiological factors such as environmental stimuli/insults, oxidative stress, genetic predisposition, comorbidities, and eye rubbing. A series of studies using corneal tissues (epithelium, stroma), cultured corneal fibroblasts/keratocytes, tear fluid, aqueous humor, and blood from KC subjects has reported significant alterations in various biochemical factors such as extracellular matrix components, cellular homeostasis regulators, inflammatory factors, hormones, metabolic products, and chemical elements. It has become apparent that alterations in the biochemical mediators (related to various etiologies) could contribute to KC pathogenesis by altering the dynamics of extracellular matrix remodeling events such as collagen deposition, degradation, and cross-linking in the cornea. Determining key disease contributing biochemical mediators would aid in disease monitoring, prediction or abatement of disease progression, and development of targeted therapeutics to improve disease prognosis.

To determine the levels of dopamine in tear fluid and demonstrate the use of tear fluid as a non-invasive source for dopamine measurements in humans. The study cohort included 30 clinically healthy individuals without any pre-existing ocular or systemic conditions. Matched tear fluid (using Schirmer's strips and capillary tubes) and plasma were collected from the subjects. Dopamine levels were evaluated using direct competitive chemiluminescent enzyme-linked immunosorbent assay (ELISA), dopamine kit (Cloud Clone Corp, TX, USA). Significantly higher dopamine levels were found in the tear fluid compared to plasma in the study subjects. The level of dopamine was 97.2 ± 11.80 pg/ml (mean ± SEM), 279 ± 14.8 pg/ml (mean ± SEM), and 470.4 ± 37.64 pg/ml (mean ± SEM) in the plasma and in the tears collected using Schirmer's strips and capillary tubes, respectively. Dopamine was detectable in all the tear fluid samples tested and was also found to be at a higher concentration than in plasma samples. Tear fluid can be used as a non-invasive sample source to monitor dopamine levels.