Investigative ophthalmology & visual science最新文献

{"title":"Downregulation of SARM1 Protects Retinal Ganglion Cell Axonal and Somal Degeneration Via JNK Activation in a Glaucomatous Model of Ocular Hypertension.","authors":"Xuejin Zhang, Ting Li, Rong Zhang, Junfeng Li, Kaidi Wang, Jihong Wu","doi":"10.1167/iovs.65.13.7","DOIUrl":"10.1167/iovs.65.13.7","url":null,"abstract":"<p><strong>Purpose: </strong>This study aimed to assess the expression of sterile alpha and TIR motif containing protein 1 (SARM1) in both chronic and acute glaucomatous animal models and investigate the underlying SARM1-JNK signaling mechanism responsible for the protective effects of SARM1 downregulation on retinal ganglion cell (RGC) soma and axons in a chronic intraocular hypertension (COH) model.</p><p><strong>Methods: </strong>The COH model was induced by injecting magnetic microbeads into the anterior chamber, whereas the acute model was created through ischemia-reperfusion (I/R) injury. Immunohistochemistry and Western blot were used to assess SARM1 expression and JNK phosphorylation in the retina and optic nerve. SARM1 downregulation was achieved through the intravitreal injection of adeno-associated virus (AAV)2-shRNA. Quantitative analysis of RGC survival was performed by the counting of Brn3A-positive RGCs, and surviving axons were assessed through optic nerve toluidine blue stain.</p><p><strong>Results: </strong>The expression of SARM1 increased 1 week after microbead injection in the optic nerve, whereas the retinal SARM1 expression decreased at 3 days post-injection in the COH model. After 24 hours of reperfusion, SARM1 expression increased in both the optic nerves and the retinas in the I/R injury model. SARM1 downregulation led to increased survival of RGC soma and axons in the COH model. In this model, JNK phosphorylation was significantly reduced concomitant with decreased SARM1 expression.</p><p><strong>Conclusions: </strong>Elevated SARM1 expression was observed in the optic nerves in both the COH and I/R injury models. Downregulation of SARM1 exhibited a protective effect on RGC soma and axons in the COH model, with JNK identified as a downstream regulator of SARM1 in this context.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"65 13","pages":"7"},"PeriodicalIF":5.0,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11540032/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142583008","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proposing a Methodology for Axon-Centric Analysis of IOP-Induced Mechanical Insult.","authors":"Manik Bansal, Bingrui Wang, Susannah Waxman, Fuqiang Zhong, Yi Hua, Yuankai Lu, Juan Reynaud, Brad Fortune, Ian A Sigal","doi":"10.1167/iovs.65.13.1","DOIUrl":"10.1167/iovs.65.13.1","url":null,"abstract":"<p><strong>Purpose: </strong>IOP-induced mechanical insult on retinal ganglion cell axons within the optic nerve head (ONH) is believed to be a key factor in axonal damage and glaucoma. However, most studies focus on tissue-level mechanical deformations, overlooking that axons are long and thin, and that their susceptibility to damage likely depends on the insult's type (e.g. stretch/compression) and orientation (longitudinal/transverse). We propose an axon-centric approach to quantify IOP-induced mechanical insult from an axon perspective.</p><p><strong>Methods: </strong>We used optical coherence tomography (OCT) scans from a healthy monkey eye along with histological images of cryosections to reconstruct the axon-occupied volume including detailed lamina cribrosa (LC) pores. Tissue-level strains were determined experimentally using digital volume correlation from OCT scans at baseline and elevated IOPs, then transformed into axonal strains using axon paths estimated by a fluid mechanics simulation.</p><p><strong>Results: </strong>Axons in the LC and post-LC regions predominantly experienced longitudinal compression and transverse stretch, whereas those in the pre-LC and ONH rim mainly suffered longitudinal stretch and transverse compression. No clear patterns were observed for tissue-level strains.</p><p><strong>Conclusions: </strong>Our approach allowed discerning axonal longitudinal and transverse mechanical insults, which are likely associated with different mechanisms of axonal damage. The technique also enabled quantifying insult along individual axon paths, providing a novel link relating the retinal nerve fiber layer and the optic nerve through the LC via individual axons. This is a promising approach to establish a clearer connection between IOP-induced insult and glaucoma. Further studies should evaluate a larger cohort.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"65 13","pages":"1"},"PeriodicalIF":5.0,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11539975/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Determining the Relationship Between Corneal Stiffening and Tissue Dehydration After Corneal Cross-Linking.","authors":"Raymundo Rodríguez-López, Joshua N Webb, Metecan Erdi, Peter Kofinas, Walfre Franco, Hongyuan Zhang, James Bradley Randleman, Giuliano Scarcelli","doi":"10.1167/iovs.65.13.14","DOIUrl":"10.1167/iovs.65.13.14","url":null,"abstract":"<p><strong>Purpose: </strong>To quantify corneal cross-linking (CXL)-induced stiffening via mechanical testing to estimate the impact of changes in hydration levels (H) and evaluate depth-dependent tissue hydration after CXL.</p><p><strong>Methods: </strong>Eighty-three porcine corneal buttons were divided into three groups: Standard protocol CXL (S-CXL), accelerated CXL (A-CXL), and untreated (nonirradiated riboflavin-only) controls. Samples were hydrated or dehydrated to modulate H and dynamic mechanical analyzer compression tests were performed to measure Young's modulus (E). To extract the solid tissue network modulus, the cornea was modeled as a biphasic material after measuring E at different H. Corneal hydration was correlated with depth-dependent tissue thickness characterized by confocal reflection microscopy (CRM).</p><p><strong>Results: </strong>Young's modulus increased fourfold after S-CXL (0.72 ± 0.1 MPa) and threefold after A-CXL E (0.53 ± 0.12 MPa) versus controls (0.17 ± 0.045 MPa). However, H decreased from 4.07 ± 0.35 in controls to 2.06 ± 0.2 after S-CXL and 2.79 ± 0.12 after A-CXL. After H modulation and biphasic mechanical modeling, Young's modulus for corneal solid tissue network showed only a 1.8-fold increase after S-CXL (2.25 MPa) and 1.5-fold increase after A-CXL (1.85 MPa) versus controls (1.22 MPa). With CRM, the overall thickness of the corneal tissue was found to linearly correlate to hydration H as expected. No appreciable depth dependence of hydration-induced thickness changes throughout the corneal buttons were observed.</p><p><strong>Conclusions: </strong>Corneal tissue hydration changes significantly impact measured corneal stiffness after CXL using mechanical testing. Not considering H leads to major overestimation of the stiffening effect of the CXL procedure. Depth-dependence of corneal thickness because of changing hydration is strongly dependent on the integrity of the tissue.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"65 13","pages":"14"},"PeriodicalIF":5.0,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11549923/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582981","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"γδ T17 Cells Regulate the Acute Antiviral Response of NK Cells in HSV-1-Infected Corneas.","authors":"Rachel R Rodenberg, Domenico Spadafora, Steffani Fitzpatrick, Grant Daly, Robert Lausch, Robert A Barrington","doi":"10.1167/iovs.65.13.16","DOIUrl":"10.1167/iovs.65.13.16","url":null,"abstract":"<p><strong>Purpose: </strong>To determine whether γδ T cells regulate natural killer (NK) cells in the herpes simplex virus 1 (HSV-1)-infected cornea.</p><p><strong>Methods: </strong>CD57Bl/6 (wild-type [WT]), TCRδ-/-, and IFN-γ-/- mice were infected intracorneally with HSV-1. TCR-/- mice were treated with IL-17A at 24 hours post-infection (PI), and the WT mice received treatments of fingolimod (FTY720) and anti-IL-17A. At 48 hours PI, corneas were excised, and intracellular staining flow cytometry was performed, as well as multiplex analysis. Additionally, single-cell RNA sequencing (scRNAseq) was done to analyze the transcriptome of NK cells from WT and TCRδ-/- mice.</p><p><strong>Results: </strong>In mice lacking γδ T cells, there were significantly fewer NK cells following ocular HSV-1 infection. This reduction of NK cells corresponded with lower levels of cytokines and chemokines associated with the antiviral response. Furthermore, NK cells from WT mice had enriched IL-17A signaling compared to those from TCRδ-/- mice. The NK cell response was partially rescued in TCRδ-/- mice by administration of IL-17A. Correspondingly, the NK cell response could be blunted in WT mice by administration of anti-IL-17A. Finally, IFN-γ-/- mice had significantly less IL-17A production compared to WT mice.</p><p><strong>Conclusions: </strong>γδ T17 cells promote NK cell accumulation in HSV-1-infected corneas. In turn, NK cells secrete IFN-γ, which negatively regulates further IL-17A production by γδ T cells.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"65 13","pages":"16"},"PeriodicalIF":5.0,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11549926/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142583054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PINK1/Parkin-Mediated Mitophagy Ameliorates Mitochondrial Dysfunction in Lacrimal Gland Acinar Cells During Aging.","authors":"Han Zhao, Yue Zhang, Yujie Ren, Wanpeng Wang","doi":"10.1167/iovs.65.13.12","DOIUrl":"10.1167/iovs.65.13.12","url":null,"abstract":"<p><strong>Purpose: </strong>Aging alters the function of the lacrimal gland and disrupts the balance of the microenvironment on the ocular surface, eventually leading to aqueous-tear-deficient dry eye. Mitophagy has been reported to play an important role in aging, but the underlying mechanism remains unclear.</p><p><strong>Methods: </strong>The young (6 weeks) and middle-aged (12 months) male C57BL/6J mice were used in this study, and mitophagy agonist rapamycin and inhibitor Mdivi-1 were used in in vivo experiments. Hematoxylin and eosin, Masson, Oil Red O, and reactive oxygen species (ROS) staining were used to detect histological changes and lipids in lacrimal gland. Changes in the expression of proteins were identified by Western blotting of lacrimal gland lysates. Transmission electron microscopy and immunofluorescence staining were used to assess mitophagy. The single-cell RNA sequencing (scRNA-seq) and bioinformatics analyses were used to detect transcription signature changes during aging.</p><p><strong>Results: </strong>In this study, we discovered that aging increased oxidative stress, which increased apoptosis, and generated ROS in acinar epithelial cells. Furthermore, activation of PINK1/Parkin-mediated mitophagy by rapamycin reduced lacrimal gland ROS concentrations and prevented aging-induced apoptosis of acinar cells, thereby causing histological alterations, microstructural degradation, and increasing tear secretion associated with ROS accumulation. By contrast, Mdivi-1 aggregates mitochondrial function and thereafter leads to lacrimal gland function impairment by inhibiting mitochondrial fission and giving rise to mitophagy.</p><p><strong>Conclusions: </strong>Overall, our findings suggested that aging could impair mitochondrial function of acinar cells, and age-related alterations may be treated with therapeutic approaches that enhance mitophagy while maintaining mitochondrial function.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"65 13","pages":"12"},"PeriodicalIF":5.0,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11549928/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142583016","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Silencing METTL3 Increases HSP70 Expression and Alleviates Fibrosis in Keratocytes.","authors":"Yapeng Jing, Jun Li, Peng Hao, Shulei Xing, Xuan Li","doi":"10.1167/iovs.65.13.9","DOIUrl":"10.1167/iovs.65.13.9","url":null,"abstract":"<p><strong>Purpose: </strong>To explore the potential role of N6-methyladenosine (m6A) and its regulatory factors in corneal fibrosis response using both in vivo and in vitro models.</p><p><strong>Methods: </strong>This study utilized the C57BL/6 mouse corneal alkali burn as an in vivo model and stimulated keratocytes with transforming growth factor beta 1 (TGF-β1) in vitro. Small interfering RNA (siRNA) was employed to downregulate the expression of YTH domain family member 2 (YTHDF2), methyltransferase-like 3 (METTL3), and fat mass and obesity-associated protein (FTO) in keratocytes. The expression of relevant genes was quantified by real-time quantitative reverse-transcription PCR (qRT-PCR), western blotting, and immunohistochemistry.</p><p><strong>Results: </strong>After an alkali burn, m6A modification in corneas increased, with the most notable increase observed on the fourth day after the injury. The levels of METTL3 and FTO initially decreased and then increased. After 21 days following an alkali burn, the corneal fibrosis was most significant. The levels of METTL3 and FTO were elevated. There were higher levels in m6A modification and the expression of METTL3 and FTO in keratocytes stimulated by TGF-β1. In corneas after alkali burns and in keratocytes stimulated by TGF-β1, the expression of heat shock protein 70 (HSP70) was negatively correlated with fibrotic response markers. Silencing METTL3 and YTHDF2 in keratocytes increased HSP70 expression and reduced the expression of fibrosis-related indicators in keratocytes stimulated by TGF-β1. However, silencing FTO did not significantly affect the expression of HSP70 and fibrosis.</p><p><strong>Conclusions: </strong>These findings indicate that METTL3 is involved in the modulation of corneal fibrosis through the regulation of HSP70 expression in a manner that is dependent on YTHDF2.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"65 13","pages":"9"},"PeriodicalIF":5.0,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11562871/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142583040","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the Relationship Between Refractive Errors and Common Chronic Diseases Via Blood Biochemistry Tests: A Large Prospective Cohort Study.","authors":"Yanze Yu, Hao Chen, Zhanying Wang, Yuhao Ye, Zhe Zhang, Yongle Bao, Yingnan Jia, Xingtao Zhou, Jing Zhao","doi":"10.1167/iovs.65.13.26","DOIUrl":"10.1167/iovs.65.13.26","url":null,"abstract":"<p><strong>Purpose: </strong>The purpose of this study was to examine the association between refractive errors and common chronic diseases using blood biochemistry tests, and to investigate the associated modifiable risk factors, with the goal of informing and developing effective preventive strategies.</p><p><strong>Methods: </strong>A total of 116,245 participants with refractometry at baseline enrolled in the UK Biobank were included in this prospective cohort study. Restricted cubic spline and Cox proportional hazards models were used to detect associations between refractive error, blood biochemistry tests, and common chronic diseases. Interaction effects on the additive scale and effect modification analysis were used to explore excess modifiable risk factors for disease prevention.</p><p><strong>Results: </strong>Spherical equivalent significantly associated with vitamin D, sex hormone binding globulin, apolipoprotein A, blood glucose, and aspartate aminotransferase levels. Subjects with myopia demonstrated a 13% higher risk of type 2 diabetes mellitus (T2DM) incidence compared to those without myopia (hazard ratio [HR] = 1.13, 95% confidence interval [CI] = 1.08-1.19) throughout a median follow-up of 9.12 years. Interaction analysis revealed 15% (95% CI = 9%-21%) of this risk was due to myopia-obesity interaction. However, active engagement in physical activity could potentially mitigate this risk (HR = 1.06, 95% CI = 0.93-1.20).</p><p><strong>Conclusions: </strong>Refractive errors were associated with specific blood indicators, particularly noting the association between myopia and higher T2DM incidence in middle-aged and elderly populations. This effect interacts with obesity, and promoting physical activity among myopia individuals provides greater benefits in the prevention of T2DM compared to non-myopic individuals.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"65 13","pages":"26"},"PeriodicalIF":5.0,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11572752/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142620766","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Erratum in: IMI - Defining and Classifying Myopia: A Proposed Set of Standards for Clinical and Epidemiologic Studies.","authors":"","doi":"10.1167/iovs.65.13.19","DOIUrl":"10.1167/iovs.65.13.19","url":null,"abstract":"","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"65 13","pages":"19"},"PeriodicalIF":5.0,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11552052/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142604458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tapinarof, an Aryl Hydrocarbon Receptor Ligand, Mitigates Fibroblast Activation in Thyroid Eye Disease: Implications for Novel Therapy.","authors":"Charkira C Patrick, Elisa Roztocil, Farha Husain, Steven E Feldon, Collynn F Woeller","doi":"10.1167/iovs.65.13.40","DOIUrl":"10.1167/iovs.65.13.40","url":null,"abstract":"<p><strong>Purpose: </strong>In thyroid eye disease (TED), activation and proliferation of orbital fibroblasts (OFs) promotes remodeling and causes an increase in the volume of orbital tissue. Platelet-derived growth factors (PDGFs) are elevated in TED and promote OF activation. The aryl hydrocarbon receptor (AHR), a ligand activated nuclear receptor, is important in regulating OF activation. AHR ligands have been evaluated as therapeutic agents for inflammatory diseases. Here, we hypothesize that AHR ligands will block PDGF-induced signaling in TED OFs.</p><p><strong>Methods: </strong>OFs from both non-TED and TED patients were treated with PDGFβ, with or without the AHR ligands 6-Formylindolo[3,2-b]carbazole (FICZ) or tapinarof. Cell viability was measured by the Alamar Blue assay. Cell proliferation was quantified using the BrdU assay. Cell lysates were collected and analyzed by Western blotting and real-time quantitative PCR (RT-qPCR) to measure PDGF and AHR signaling. Scratch assays were used to measure OF migration.</p><p><strong>Results: </strong>PDGFβ induced proliferation in TED OFs significantly more than in non-TED OFs. Additionally, PDGFβ increased phosphorylation of AKT and expression of thymidylate synthase (TYMS). PDGFβ dependent proliferation and downstream signaling were attenuated by FICZ or tapinarof. TYMS and other PDGF target genes were upregulated by PDGFβ and reduced by AHR activation. PDGFβ induced TED OF migration while both FICZ and tapinarof diminished this effect.</p><p><strong>Conclusions: </strong>PDGF signaling led to increased proliferation and activation of TED OFs. Treatment of TED OFs with the AHR ligands, FICZ and tapinarof, mitigated PDGF induced effects. These studies support the concept that AHR and PDGF signaling could form the basis for new TED therapeutics.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"65 13","pages":"40"},"PeriodicalIF":5.0,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11578154/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142668078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of Lysyl Oxidase-Like Protein 3 in the Pathogenesis of Graves' Orbitopathy in Orbital Fibroblasts.","authors":"Seung Hyun Park, Soo Hyun Choi, Hyun Young Park, JaeSang Ko, Jin Sook Yoon","doi":"10.1167/iovs.65.13.33","DOIUrl":"10.1167/iovs.65.13.33","url":null,"abstract":"<p><strong>Purpose: </strong>The lysyl oxidase (LOX) family has been implicated in the pathogenesis of diseases caused by inflammation and fibrosis. Therefore, we aimed to examine the role of lysyl oxidase-like protein 3 (LOXL3) in Graves' orbitopathy (GO) pathogenesis and its potential as a treatment target.</p><p><strong>Methods: </strong>Quantitative real-time polymerase chain reaction compared the transcript levels of the five LOX family subtypes in orbital tissue explants obtained from patients with GO (n = 18) and healthy controls (n = 15). The effects of LOXL3 inhibition on interleukin (IL)-1β-induced proinflammatory cytokines, transforming growth factor (TGF)-β-induced profibrotic proteins, intracellular signaling molecules, and adipogenic markers were evaluated using Western blotting. Adipogenic differentiation was identified using Oil Red O staining.</p><p><strong>Results: </strong>LOX and LOXL3 transcript levels were high in GO tissues. Stimulation with IL-1β, TGF-β, and insulin-like growth factor-1 significantly increased LOXL3 messenger RNA expression in GO fibroblasts. Furthermore, silencing LOXL3 attenuated the IL-1β-induced production of proinflammatory cytokines (IL-6, IL-8, and intercellular adhesion molecule-1) and TGF-β-induced production of profibrotic proteins (fibronectin, collagen 1α, and alpha-smooth muscle actin). It also reduced the IL-1β or TGF-β-induced expression of phosphorylated nuclear factor kappa-light-chain-enhancer of activated B cells, protein kinase B, extracellular signal-regulated kinase, and c-Jun N-terminal kinase. Additionally, LOXL3 silencing suppressed adipocyte differentiation and the expression of adipogenic transcription factors (leptin, AP-2, peroxisome proliferator-activated receptor gamma, and CCAAT/enhancer-binding protein).</p><p><strong>Conclusions: </strong>LOXL3 is crucial in GO pathogenesis. LOXL3 inhibition reduced inflammatory cytokine production, fibrotic protein expression, and fibroblast differentiation into adipocytes. This study highlights LOXL3 as a potential therapeutic target for GO.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":"65 13","pages":"33"},"PeriodicalIF":5.0,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11578161/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638896","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}