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Dry eye is one of the most common ocular surface diseases in the world and seriously affects the quality of life of patients. As an immune-related disease, the mechanism of dry eye has still not been fully elucidated. The cGAS-STING pathway is a recently discovered pathway that plays an important role in autoimmune and inflammatory diseases by reco...
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... sensing dsDNA, the cGAS-STING pathway has become a key pathway in autoimmune and inflammatory diseases ( Table 1), such as Sjogren's syndrome (52), systemic lupus erythematosus (SLE) (45), and multiple sclerosis (53). As a downstream target of the cGAS-STING pathway, type I interferon serves as a marker and potential therapeutic target of systemic autoimmune diseases (54, 55). ...Citations
... NF-κB activation pathways release pro-inflammatory cytokines (such as IL-1b, IL-2, IL-6, IL-8, IL-12, and TNF-α) and chemokines (MCP-1, IL-18, and CXCL 10), which can not only trigger an inflammatory response but also lead to goblet cell loss. Both pathways also induce the expression of adhesion molecules (ICAM-1, VCAM-1, and MMPs) that activate T-cell migration and result in corneal-barrier disruption and differentiation of CD4+T cells to T-helper cells [66]. The extent and effects of chronic inflammation combined with the dysfunction and loss of conjunctival goblet cells decrease the mucin levels present in human tears [50]. ...
The aim of this work was to assess the tolerability, safety, and efficacy of an ophthalmic topical formulation containing helenalin from Arnica montana and hyaluronic acid 0.4% (HA) in patients with mild-to-moderate Dry Eye Disease (DED) exhibiting positive Matrix Metalloproteinase 9 (MMP-9) test results. Tolerability and safety were evaluated in 24 healthy subjects. Participants were instructed to apply one drop of the formulation three times a day in the study eye, for 2 weeks, followed by a clinical follow-up of 21 days. Efficacy was studied in 48 DED patients randomized into Study (Group 1/receiving the studied formulation) or Control (Group 2/Receiving HA 0.4% eye lubricant) groups for 1 month. Assessments included an MMP-9 positivity test, conjunctival impression cytology (CIC), Ocular Surface Disease Index (OSDI), non-invasive film tear breakup time (NIBUT), non-invasive average breakup time (NIAvg-BUT), ocular surface staining, Schirmer’s test, and meibomiography. A crossover design with an additional 1-month follow-up was applied to both groups. Healthy subjects receiving the studied formulation exhibited good tolerability and no adverse events. Regarding the efficacy study, Group 1 exhibited a statistically significant reduction in the MMP-9 positivity rate compared to Group 2 (p < 0.001). Both Group 1 and Group 2 exhibited substantial improvements in OSDI and NIBUT scores (p < 0.001). However, Group 1 demonstrated a significant improvement in NI-Avg-BUT and Schirmer’s test scores (p < 0.001), whereas Group 2 did not (p > 0.05). Finally, after the crossover, the proportion of MMP-9-positive subjects in Group 1 increased from 25% to 91.6%, while Group 2 showed a significant decrease from 87.5% to 20.8%. Overall, the topical formulation containing sesquiterpene helenalin from Arnica montana and hyaluronic acid was well tolerated and exhibited a favorable safety profile. Our formulation reduces DED symptomatology and modulates the ocular surface inflammatory process; this is evidenced by the enhancement of CIC, the improvement of DED-related tear film status, and the reduction of the MMP-9 positivity rate.
... For example, some people [24] clarify the inhibitory effect of mesenchymal stem cells on xerophthalmia by inhibiting autophagy markers in SS mouse model. CGAS-STING pathway [25] is a newly discovered pathway, which can play an important role in autoimmune and inflammatory diseases by identifying dsDNA, and can be further studied. In terms of hormones, there are relatively few studies on the occurrence of sex hormones in xerophthalmia, some of which have found that androgens play a certain role in the treatment of xerophthalmia, [26] so the future development of androgens is a potential hot spot. ...
Background
Dry eye is a chronic ocular surface disease caused by the instability of tear film or the imbalance of the ocular surface microenvironment which can lead to a diverse range of ocular discomfort symptoms. At present, the relevant mechanism of autoimmunity and treatment of dry eye is still unclear. Due to the proliferation of research papers in this field, visual analysis of existing papers can provide reference for future research.
Methods
The academic papers of Web of Science were searched with the topics of “autoimmunity” and “dry eye,” and the countries, institutions and keywords of the literatures selected in this domain were visualized by Citespace and Vosviewer software.
Results
A total of 787 valid international papers were detected, and the publication count exhibited a consistent upward trend year by year. Within this field, the US has produced the highest number of papers (363), with Baylor College of Medicine being the most prolific institution (28 publications). High-producing authors in this field include Artemis P. Simopoulos and Stephen C. Pflugfelder.
Conclusion
International research in this field has focused on the pathogenesis, symptoms, and treatment of dry eye. It is predicted that the future international research hotspots will be the pathophysiology of autoimmune dry eye disease, data analysis of artificial intelligence-related diseases, and research on improving patients’ quality of life.
... In a previous study, we speculated that mitochondrial DNA released into the cytoplasm may cause inflammation via the cGAS-STING signaling pathway under hyperosmotic stress (HS). 34 In this study, we have provided evidence for the activation of the cGAS-STING pathway by mitochondrial DNA sensing, which mediates ocular surface inflammation in two experimental dry eye models -a mouse ocular surface treated with BAC and a mouse model with surgically removed lacrimal glands, as well as dry eye patient samples-along with cultured HCE exposed to hyperosmotic stress (HS-HCE). This study represents the first investigation of this novel pathway in ocular surface diseases, offering a new perspective on inflammatory responses occurring at the ocular surface. ...
The innate immune response is the main pathophysiological process of ocular surface diseases exposed to multiple environmental stresses. The epithelium is central to the innate immune response, but whether and how innate immunity is initiated by ocular epithelial cells in response to various environmental stresses in ocular surface diseases, such as dry eye, is still unclear. By utilizing two classic experimental dry eye models-a mouse ocular surface treated with benzalkonium chloride (BAC) and a mouse model with surgically removed extraorbital lachrymal glands, as well as dry eye patient samples-along with human corneal epithelial cells (HCE) exposed to hyperosmolarity, we have discovered a novel innate immune pathway in ocular surface epithelial cells. Under stress, mitochondrial DNA (mtDNA) was released into the cytoplasm through the mitochondrial permeability transition pore (mPTP) and further activated the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, aggravating downstream inflammatory responses and ocular surface damage. Genetic deletion or pharmacological suppression of STING and inhibition of mtDNA release reduced inflammatory responses, whereas mtDNA transfection supported cytoplasmic mtDNA-induced inflammatory responses by activating the cGAS-STING pathway. Our study clarified the cGAS-STING pathway-dependent sensing of mitochondrial DNA-mediated ocular surface inflammation, which elucidated a new mechanism of ocular surface diseases in response to multiple environmental stresses.
... Oxidative stress and hyperosmolarity contribute to CIOS by activating the NF-κB pathway, resulting in the release of pro-inflammatory cytokines, chemokines, and matrix metalloproteinases (MMPs) (46)(47)(48)(49). This chronic inflammation damages the cornea and conjunctiva, leading to symptoms and ocular surface damage (50)(51)(52)(53)(54). MMP-9 levels are elevated in DED, contributing to goblet cell depletion and sustained inflammation (55)(56)(57)(58). ...
Purpose: To assess the tolerability, safety, and efficacy of an ophthalmic topical formulation containing helenalin from Arnica montana and hyaluronic acid 0.4% (HA) in patients with mild to moderate dry eye disease (DED) exhibiting positive Matrix Metalloproteinase 9 (MMP-9) test results. Methods: Tolerability and safety were evaluated in 24 healthy subjects. Participants were in-structed to routinely apply one drop of the formulation three times a day in the study eye, for a period of two weeks, followed by a clinical follow-up of 21 days. Efficacy was studied in 48 DED patients randomized into Study (Group 1/ receiving the study formulation) or Control (Group 2/ Receiving HA 0.4% eye lubricant) groups, for 4 weeks. Assessments included MMP-9 positivity, conjunctival impression cytology (CIC), Ocular Surface Disease Index (OSDI), non-invasive tear film breakup time (NIF-BUT), non-invasive average breakup time (NIAvg-BUT), ocular surface staining, Schirmer's test, and meibomiography. A crossover design with a four-week follow-up was applied to the control group. Results: Healthy subjects receiving the study formulation exhibited good tolerability and no ad-verse events. Group 1 showed significant MMP-9 reduction (25% positivity rate) unlike Group 2 (87.5% positivity rate). Group 1 displayed improved CIC (33.3% vs. 0% SSD) compared to Group 2 (29.1%). OSDI and NIF-BUT scores improved in both groups (p < 0.001). Only Group 1 showed improved NIAvg-BUT and Schirmer’s test scores (p < 0.001), while Group 2 did not (p > 0.05). MMP-9-positive subjects shifted from 25% to 91.6% in Group 1 and 87.5% to 20.8% in Group 2 after the follow-up. Conclusion: The topical formulation containing helenalin from Arnica montana and hyaluronic acid is well tolerated and has a good safety profile. Our formulation reduces DED sympto-matology and modulates the ocular surface inflammatory process; this is evidenced by the en-hancement of CIC, the improvement of DED-related tear film status, and the reduction of MMP-9 positivity rate.
... DED is multifactorial inflammatory disorder that adversely affects patients' quality of life (Ouyang et al. 2022). Accumulating evidence has demonstrated that inflammation is a core diver of DED pathogenesis (Li et al. 2022). ...
Dry eye disease (DED) is a common inflammatory ocular surface disorder, seriously affecting the quality of life of patients. Aurantio-obtusin (AO) is a bioactive anthraquinone compound isolated from Semen Cassiae which has multiple pharmacological activities. Nonetheless, the specific function of AO in DED is unclarified. In this study, a rodent DED model was established by benzalkonium chloride (BAC) induction, followed by topical administration of AO. The results showed that topical application of AO increased tear production, mitigated ocular surface disruption and maintained the number of goblet cells in BAC-induced DED rats (p˂0.05). ELISA revealed that AO treatment significantly (p˂0.001) reduced the production of proinflammatory cytokines and chemokines in the conjunctiva and cornea of BAC-induced DED rats. Immunohistochemical staining and western blotting showed that AO treatment suppressed the expression levels of NLR family pyrin domain containing 3 (NLRP3) inflammasome-related proteins, and inhibited activation of nuclear factor kappa B (NF-κB) signaling pathway in rat conjunctiva and cornea (p˂0.001). In conclusion, AO treatment alleviates BAC-induced DED in rats by inhibiting NF-κB/NLRP3 inflammasome signaling pathway.
... The possible implication of RLRs and the cGAS-STING pathway in SS have been addressed in recent reviews (15,16). Thus, here we will focus on recent data pointing to a pivotal role of the endosomal nucleic acid-sensing TLRs and especially TLR7 in SS pathogenesis. ...
Sjögren’s syndrome (SS) is a chronic systemic autoimmune disease that affects the salivary and lacrimal glands, as well as other organ systems like the lungs, kidneys and nervous system. SS can occur alone or in combination with another autoimmune disease, such as systemic lupus erythematosus (SLE) or rheumatoid arthritis. The etiology of SS is unknown but recent studies have revealed the implication of the activation of innate immune receptors, including Toll-like receptors (TLRs), mainly through the detection of endogenous nucleic acids, in the pathogenesis of systemic autoimmune diseases. Studies on SS mouse models suggest that TLRs and especially TLR7 that detects single-stranded RNA of microbial or endogenous origin can drive the development of SS and findings in SS patients corroborate those in mouse models. In this review, we will give an overview of the function and signaling of nucleic acid-sensing TLRs, the interplay of TLR7 with TLR8 and TLR9 in the context of autoimmunity, summarize the evidence for the critical role of TLR7 in the pathogenesis of SS and present a possible connection between SARS-CoV-2 and SS.
