The gut-eye-lacrimal gland-microbiome axis in Sjogren Syndrome.
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ABSTRACT:
SUBMITTER: Trujillo-Vargas CM
PROVIDER: S-EPMC7124975 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Epithelial sodium channel (ENaC) plays a critical role in the control of Na(+) balance and the development and progression of exocrine gland pathologic condition. The aim of the present study was to investigate the presence of ENaC in the rabbit lacrimal gland (LG) and its potential changes during induced autoimmune dacryoadenitis (IAD) and pregnancy.Total messenger RNA (mRNA) of ?, ?, and ? subunits was extracted from whole LG, acinar cells, and ductal cells by laser capture microdissection (LCM) for real-time reverse-transcriptase polymerase chain reaction. Lacrimal glands were processed for Western blot and immunofluorescence.Messenger RNA for both ? and ? was expressed in whole LG lysates, whereas ? was undetectable. In rabbits with IAD, the levels of mRNA for ? and ? were 20.9% and 58.9% lower (P<0.05), whereas no significant changes were observed in term-pregnant rabbits (P=0.152). However, we were unable to detect mRNA of any subunit in LCM specimens of ductal cells because of their low levels. Western blot demonstrated bands for both ? (90 kDa) and ? (85 kDa) but ? was undetectable. In rabbits with IAD, densitometry analysis showed that expression of ? decreased 22%, whereas ? decreased 26% (P<0.05). In pregnant rabbits, however, ? expression was 31% lower, whereas ? expression was 34% lower (P<0.05). From immunofluorescence studies, all subunits were present in ductal cells, whereas virtually no immunoreactivity was detected in acini. No noticeable changes of their distribution pattern and intensity were found in rabbits with IAD or during pregnancy.The present study demonstrated the presence of ENaC in the rabbit LG and its alterations in IAD and pregnancy, suggesting that ENaC may contribute to the pathogenesis of altered LG secretion and ocular surface symptoms in these animals.
| S-EPMC4553130 | biostudies-literature
Project description:Sjögren syndrome is an autoimmune disease characterized by targeted destruction of the lacrimal and salivary glands resulting in symptoms of severe ocular and oral dryness. Despite its prevalence, the mechanisms driving autoimmune manifestations are unclear. In patients and in the nonobese diabetic (NOD) mouse model of Sjögren syndrome, lymphocytic infiltrates consist of CD4 and CD8 T cells, although the role of CD8 T cells in disease pathogenesis has been largely unexplored. Here, we evaluated the contribution of CD8 T cells to lacrimal and salivary gland autoimmunity. Within the lacrimal and salivary glands of NOD mice, CD8 T cells were proliferating, expressed an activated phenotype, and produced inflammatory cytokines. Transfer of purified CD8 T cells isolated from the cervical lymph nodes (LNs) of NOD mice into NOD-severe combined immunodeficiency recipients resulted in inflammation of the lacrimal glands, but was not sufficient to cause inflammation of the salivary glands. Lacrimal gland-infiltrating CD8 T cells displayed a cytotoxic phenotype, and epithelial cell damage in the lacrimal glands was observed in recipients of CD8 T cells regardless of the presence of CD4 T cells. Collectively, our results demonstrate that CD8 T cells have a pathogenic role in lacrimal gland autoimmunity. The gland-specific pathogenicity of CD8 T cells makes them a valuable resource to further understand the mechanisms that discriminate lacrimal versus salivary gland autoimmunity and for the development of new therapeutics that target the early stages of disease.
| S-EPMC5595634 | biostudies-literature
Project description:PurposeTo evaluate the efficacy of topical rapamycin in treating autoimmune dacryoadenitis in a mouse model of Sjögren's syndrome.MethodsWe developed rapamycin in a poly(ethylene glycol)-distearoyl phosphatidylethanolamine (PEG-DSPE) micelle formulation to maintain solubility. Rapamycin or PEG-DSPE eye drops (vehicle) were administered in a well-established Sjögren's syndrome disease model, the male nonobese diabetic (NOD) mice, twice daily for 12 weeks starting at 8 weeks of age. Mouse tear fluid was collected and tear Cathepsin S, a putative tear biomarker for Sjögren's syndrome, was measured. Lacrimal glands were retrieved for histological evaluation, and quantitative real-time PCR of genes associated with Sjögren's syndrome pathogenesis. Tear secretion was measured using phenol red threads, and corneal fluorescein staining was used to assess corneal integrity.ResultsLymphocytic infiltration of lacrimal glands from rapamycin-treated mice was significantly (P = 0.0001) reduced by 3.8-fold relative to vehicle-treated mice after 12 weeks of treatment. Rapamycin, but not vehicle, treatment increased tear secretion and decreased corneal fluorescein staining after 12 weeks. In rapamycin-treated mice, Cathepsin S activity was significantly reduced by 3.75-fold in tears (P < 0.0001) and 1.68-fold in lacrimal gland lysates (P = 0.003) relative to vehicle-treated mice. Rapamycin significantly altered the expression of several genes linked to Sjögren's syndrome pathogenesis, including major histocompatibility complex II, TNF-?, IFN-?, and IL-12a, as well as Akt3, an effector of autophagy.ConclusionsOur findings suggest that topical rapamycin reduces autoimmune-mediated lacrimal gland inflammation while improving ocular surface integrity and tear secretion, and thus has potential for treating Sjögren's syndrome-associated dry eye.
| S-EPMC5270623 | biostudies-literature
Project description:PurposeLacrimal gland enlargement is a common feature of thyroid eye disease (TED) and has been positively correlated with the clinical activity score. Although lacrimal gland volume is the preferred measure of lacrimal gland size, its calculation is not clinically translatable due to the expertise, time and advanced software required. The aim of our study is to determine whether the lacrimal gland volume in patients with TED undergoing magnetic resonance imaging (MRI) can be estimated using simpler lacrimal gland linear and area measurements.MethodsA retrospective review of 102 orbits (51 patients) with TED who underwent orbital MRI was conducted. The maximum length, width, and area of the lacrimal gland were measured in axial and coronal sections. Lacrimal gland volume was calculated by using a manual segmentation technique on all consecutive axial slices on commercially available software, OsiriX. All quantitative measurements were correlated with the lacrimal gland volume.ResultsMean age of participants was 59 ± 16 years, and 67% (n = 34) were females. With multivariate analyses, combined lacrimal gland axial and coronal areas strongly correlated with volume (r = 0.843, p < 0.01). Strong univariate predictors of volume included axial area (r = 0.704, p < 0.01) and coronal area (r = 0.722, p < 0.01), while moderate predictors included axial length (r = 0.523, p < 0.01), axial width (r = 0.521, p < 0.01), coronal length (r = 0.450, p < 0.01), and coronal width (r = 0.649, p < 0.01).ConclusionIn patients with thyroid eye disease, lacrimal gland volume can be estimated using axial and coronal areas, which is simpler and more time efficient than calculating volumes.
| S-EPMC10847191 | biostudies-literature
Project description:PurposeDry eye syndrome (DES) is a prevalent postoperative complication after myopic corneal refractive surgeries and the main cause of postoperative dissatisfaction. Although great efforts have been made in recent decades, the molecular mechanism of postoperative DES remains poorly understood. Here, we used a series of bioinformatics approaches and experimental methods to investigate the potential mechanism involved in postoperative DES.MethodsBALB/c mice were randomly divided into sham, unilateral corneal nerve cutting (UCNV) + saline, UCNV + vasoactive intestinal peptide (VIP), and UCNV + ferrostatin-1 (Fer-1, inhibitor of ferroptosis) groups. Corneal lissamine green dye and tear volume were measured before and two weeks after the surgery in all groups. Lacrimal glands were collected for secretory function testing, RNA sequencing, ferroptosis verification, and inflammatory factor detection.ResultsUCNV significantly induced bilateral decreases in tear secretion. Inhibition of the maturation and release of secretory vesicles was observed in bilateral lacrimal glands. More importantly, UCNV induced ferroptosis in bilateral lacrimal glands. Furthermore, UCNV significantly decreased VIP, a neural transmitter, in bilateral lacrimal glands, which increased Hif1a, the dominant transcription factor of transferrin receptor protein 1 (TfR1). Supplementary VIP inhibited ferroptosis, which decreased the inflammatory reaction and promoted the maturation and release of secretory vesicles. Supplementary VIP and Fer-1 improved tear secretion.ConclusionsOur data suggest a novel mechanism by which UCNV induces bilateral ferroptosis through the VIP/Hif1a/TfR1 pathway, which might be a promising therapeutic target for DES-induced by corneal refractive surgeries.
| S-EPMC10281063 | biostudies-literature
Project description:Purpose:The purpose of this study was to investigate the expression of death ligands in the lacrimal glands (LGs), identify upstream factors that regulate their expression, and determine the functional roles of these factors in the pathogenesis of dry eye disease (DED). Methods:For DED experiment, ex vivo coculture system with LG and in vivo murine model using a controlled environment chamber were utilized. C57BL/6 mice and hypoxia-inducible factor (HIF)-1? conditional knockout (CKO) mice were used. Immunohistochemical staining, polymerase chain reaction, and immunoblotting were performed to determine levels of death ligands including tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in DED-induced LGs. Additionally, acinar cell and CD45+ cell apoptosis was determined with neutralizing TRAIL treatment. Results:Desiccating stress significantly increased HIF-1? expression in LG-acinar cells. Furthermore, HIF-1? deficiency significantly enhanced the infiltration of CD45+ inflammatory cells in LG and induced LG-acinar cell death. Meanwhile, only TRAIL expression was increased in DED-LG, but abrogated in HIF-1? CKO. Interestingly, the main source of TRAIL was the CD45- LG-acinar cells, but not CD45+ immune cells after DED induction. Using ex vivo coculture system, we confirmed LG-induced apoptosis of immune cells via HIF-1?-mediated TRAIL secretion following DED. Consistent with ex vivo, the insufficiency of HIF-1? and TRAIL enhanced recruitment of inflammatory cells to the LG and subsequently exacerbated ocular surface damage in DED mice. Conclusions:Our findings offer novel insight into the regulatory function of acinar cell-derived TRAIL in limiting inflammatory damage and could be implicated in the development of potential therapeutic strategies for DED.
| S-EPMC7205192 | biostudies-literature
Project description:The lacrimal gland is the major contributor to the aqueous layer of the tear film which consists of water, electrolytes and proteins. The amount and composition of this layer is critical for the health, maintenance, and protection of the cells of the cornea and conjunctiva (the ocular surface). Small changes in the concentration of tear electrolytes have been correlated with dry eye syndrome. While the mechanisms of secretion of water, electrolytes and proteins from the lacrimal gland differ, all three are under tight neural control. This allows for a rapid response to meet the needs of the cells of the ocular surface in response to environmental conditions. The neural response consists of the activation of the afferent sensory nerves in the cornea and conjunctiva to stimulate efferent parasympathetic and sympathetic nerves that innervate the lacrimal gland. Neurotransmitters are released from the stimulated parasympathetic and sympathetic nerves that cause secretion of water, electrolytes, and proteins from the lacrimal gland and onto the ocular surface. This review focuses on the neural regulation of lacrimal gland secretion under normal and dry eye conditions.
| S-EPMC3652637 | biostudies-literature
Project description:Autophagy is known to be implicated in the pathogenesis of Sjögren syndrome (SS), but evidences are limited. We aimed to examine the levels of autophagy markers in tear film and conjunctival epithelial cells from SS dry eye patients, and analyze their correlations with clinical features. Patients with SS dry eye exhibited lower Schirmer values, lower tear breakup time, and higher ocular staining scores. In tears, ATG5 and LC3B-II/I levels were significantly higher in SS dry eye. ATG5 and LC3B-II mRNA in the conjunctiva were also elevated in SS dry eye compared with non-SS dry eye. The immunostaining of conjunctival epithelium showed a punctate pattern of ATG5 and LC3B-II in SS dry eye. These staining patterns were also observed in the lacrimal gland of SS animal models. ATG5 levels in tears and the conjunctival epithelium strongly correlated with ocular staining scores, and one month of topical corticosteroid treatment reduced both ATG5 and LC3B-II/I levels in tear film and the conjunctival epithelium of patients with SS dry eye. Our results suggest that autophagy is enhanced or dysregulated in SS and autophagy markers may be serve as both diagnostic and therapeutic biomarkers in SS dry eye.
| S-EPMC5722946 | biostudies-literature
Project description:Purpose:Sjögren syndrome is an autoimmune disease that occurs primarily in women, and is associated with lacrimal gland inflammation and aqueous-deficient dry eye. We hypothesize that sex-associated differences in lacrimal gland gene expression are very important in promoting lymphocyte accumulation in this tissue and contribute to the onset, progression, and/or severity of the inflammatory disease process. To test our hypothesis, we explored the nature and extent of sex-related differences in gene expression in autoimmune lacrimal glands. Methods:Lacrimal glands were collected from age-matched, adult, male and female MRL/MpJ-Tnfrsf6lpr (MRL/lpr) and nonobese diabetic/LtJ (NOD) mice. Glands were processed for the analysis of differentially expressed mRNAs by using CodeLink Bioarrays and Affymetrix GeneChips. Data were evaluated with bioinformatics and statistical software. Results:Our results show that sex significantly influences the expression of thousands of genes in lacrimal glands of MRL/lpr and NOD mice. The immune nature of this glandular response is very dependent on the Sjögren syndrome model. Lacrimal glands of female, as compared with male, MRL/lpr mice contain a significant increase in the expression of genes related to inflammatory responses, antigen processing, and chemokine pathways. In contrast, it is the lacrimal tissue of NOD males, and not females, that presents with a significantly greater expression of immune-related genes. Conclusions:These data support our hypothesis that sex-related differences in gene expression contribute to lacrimal gland disease in Sjögren syndrome. Our findings also suggest that factors in the lacrimal gland microenvironment are critically important in mediating these sex-associated immune effects.
| S-EPMC6262646 | biostudies-literature
Project description:PurposeSjögren syndrome is an autoimmune disorder that occurs almost exclusively in women and is associated with extensive inflammation in lacrimal tissue, an immune-mediated destruction and/or dysfunction of glandular epithelial cells, and a significant decrease in aqueous tear secretion. We discovered that androgens suppress the inflammation in, and enhance the function of, lacrimal glands in female mouse models (e.g., MRL/MpJ-Tnfrsf6lpr [MRL/lpr]) of Sjögren syndrome. In contrast, others have reported that androgens induce an anomalous immunopathology in lacrimal glands of nonobese diabetic/LtJ (NOD) mice. We tested our hypothesis that these hormone actions reflect unique, strain- and tissue-specific effects, which involve significant changes in the expression of immune-related glandular genes.MethodsLacrimal glands were obtained from age-matched, adult, female MRL/lpr and NOD mice after treatment with vehicle or testosterone for up to 3 weeks. Tissues were processed for analysis of differentially expressed mRNAs using CodeLink Bioarrays and Affymetrix GeneChips. Data were analyzed with bioinformatics and statistical software.ResultsTestosterone significantly influenced the expression of numerous immune-related genes, ontologies, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways in lacrimal glands of MRL/lpr and NOD mice. The nature of this hormone-induced immune response was dependent upon the autoimmune strain, and was not duplicated within lacrimal tissues of nonautoimmune BALB/c mice. The majority of immune-response genes regulated by testosterone were of the inflammatory type.ConclusionsOur findings support our hypothesis and indicate a major role for the lacrimal gland microenvironment in mediating androgen effects on immune gene expression.
| S-EPMC6528840 | biostudies-literature