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المؤلفون: Wynne Weston-Davies, Virginia L. Calder, Malihe Eskandarpour, Sarah E. Coupland, Miles A. Nunn, Yi-Hsing Chen
المصدر: The American Journal of Pathology. 191:320-334
مصطلحات موضوعية: 0301 basic medicine, education.field_of_study, Retina, Chemistry, Leukotriene B4, Receptor expression, Leukotriene B4 receptor, Population, Retinal, respiratory system, Pathology and Forensic Medicine, 03 medical and health sciences, chemistry.chemical_compound, 030104 developmental biology, 0302 clinical medicine, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cancer research, medicine, lipids (amino acids, peptides, and proteins), education, Receptor, Lymph node
الوصف: Nomacopan, a drug originally derived from tick saliva, has dual functions of sequestering leukotriene B4 (LTB4) and inhibiting complement component 5 (C5) activation. Nomacopan has been shown to provide therapeutic benefit in experimental autoimmune uveitis (EAU). Longer acting forms of nomacopan were more efficacious in mouse EAU models, and the long-acting variant that inhibited only LTB4 was at least as effective as the long-acting variant that inhibited both C5 and LTB4, preventing structural damage to the retina and a significantly reducing effector T helper 17 cells and inflammatory macrophages. Increased levels of LTB4 and C5a (produced upon C5 activation) were detected during disease progression. Activated retinal lymphocytes were shown to express LTB4 receptors (R) in vitro and in inflamed draining lymph nodes. Levels of LTB4R-expressing active/inflammatory retinal macrophages were also increased. Within the draining lymph node CD4+ T-cell population, 30% expressed LTB4R+ following activation in vitro, whereas retinal infiltrating cells expressed LTB4R and C5aR. Validation of expression of those receptors in human uveitis and healthy tissues suggests that infiltrating cells could be targeted by inhibitors of the LTB4-LTB4 receptor 1 (BLT1) pathway as a novel therapeutic approach. This study provides novel data on intraocular LTB4 and C5a in EAU, their associated receptor expression by retinal infiltrating cells in mouse and human tissues, and in attenuating EAU via the dual inhibitor nomacopan.
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::7a64a7e26ecb63b7fe16916c92b9a531Test
https://doi.org/10.1016/j.ajpath.2020.10.010Test -
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المصدر: Cells, Vol 10, Iss 396, p 396 (2021)
Cellsمصطلحات موضوعية: Vascular Endothelial Growth Factor A, 0301 basic medicine, BLT1, LTB4, Leukotriene B4, Receptors, Leukotriene B4, Inflammation, Vascular permeability, Review, neovascularisation, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, medicine, Animals, Humans, lcsh:QH301-705.5, Leukotriene, Retinal vasculitis, business.industry, Retinal, General Medicine, medicine.disease, VEGF, Disease Models, Animal, 030104 developmental biology, chemistry, lcsh:Biology (General), inflammation, EAU, Intraocular fluid, retinal vasculitis, Immunology, 030221 ophthalmology & optometry, uveitis, medicine.symptom, business, Uveitis
الوصف: Retinal vascular diseases have distinct, complex and multifactorial pathogeneses yet share several key pathophysiological aspects including inflammation, vascular permeability and neovascularisation. In non-infectious posterior uveitis (NIU), retinal vasculitis involves vessel leakage leading to retinal enlargement, exudation, and macular oedema. Neovascularisation is not a common feature in NIU, however, detection of the major angiogenic factor—vascular endothelial growth factor A (VEGF-A)—in intraocular fluids in animal models of uveitis may be an indication for a role for this cytokine in a highly inflammatory condition. Suppression of VEGF-A by directly targeting the leukotriene B4 (LTB4) receptor (BLT1) pathway indicates a connection between leukotrienes (LTs), which have prominent roles in initiating and propagating inflammatory responses, and VEGF-A in retinal inflammatory diseases. Further research is needed to understand how LTs interact with intraocular cytokines in retinal inflammatory diseases to guide the development of novel therapeutic approaches targeting both inflammatory mediator pathways.
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::45866ee086c0a84b1966b4c31f4a94cbTest
https://www.mdpi.com/2073-4409/10/2/396Test -
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المؤلفون: Malihe Eskandarpour, Yi Hsing Chen, Virginia L. Calder, G. Galatowicz, Xiaozhe Zhang, John Greenwood, Susan Lightman
المصدر: Journal of Neuroinflammation, Vol 18, Iss 1, Pp 1-13 (2021)
Journal of Neuroinflammationمصطلحات موضوعية: Leukocyte migration, Endothelium, T cell, Phenylalanine, Experimental autoimmune uveitis, Immunology, Blood–retinal barrier, Mice, Transgenic, Pharmacology, Integrin alpha4beta1, lcsh:RC346-429, Flow cytometry, Autoimmune Diseases, Uveitis, 03 medical and health sciences, Cellular and Molecular Neuroscience, Mice, 0302 clinical medicine, Immune system, Drug Delivery Systems, Piperidines, Blood-Retinal Barrier, medicine, Animals, Humans, Integrin (α4β1, Th17 cells, Cells, Cultured, lcsh:Neurology. Diseases of the nervous system, Inflammatory monocytes/macrophages, medicine.diagnostic_test, Dose-Response Relationship, Drug, business.industry, General Neuroscience, Research, VLA-4), VLA-4, medicine.disease, Mice, Inbred C57BL, medicine.anatomical_structure, Neurology, 030221 ophthalmology & optometry, Female, business, 030217 neurology & neurosurgery
الوصف: Background The integrin VLA-4 (α4β1) plays an important role in leukocyte trafficking. This study investigated the efficacy of a novel topical α4β1 integrin inhibitor (GW559090, GW) in a mouse model for non-infectious posterior uveitis (experimental autoimmune uveitis; EAU) and its effect on intraocular leukocyte subsets. Methods Mice (female; B10.RIII or C57Bl/6; aged 6–8 weeks) were immunized with specific interphotoreceptor retinoid-binding protein (IRBP) peptides to induce EAU. Topically administered GW (3, 10, and 30 mg/ml) were given twice daily either therapeutically once disease was evident, or prophylactically, and compared with vehicle-treated (Veh) and 0.1% dexamethasone-treated (Dex) controls. Mice were sacrificed at peak disease. The retinal T cell subsets were investigated by immunohistochemistry and immunofluorescence staining. The immune cells within the retina, blood, and draining lymph nodes (dLNs) were phenotyped by flow cytometry. The effect of GW559090 on non-adherent, adherent, and migrated CD4+ T cell subsets across a central nervous system (CNS) endothelium was further assayed in vitro and quantitated by flow cytometry. Results There was a significant reduction in clinical and histological scores in GW10- and Dex-treated groups as compared to controls either administered therapeutically or prophylactically. There were fewer CD45+ leukocytes infiltrating the retinae and vitreous fluids in the treated GW10 group (P < 0.05). Immunofluorescence staining and flow cytometry data identified decreased levels of retinal Th17 cells (P ≤ 0.001) in the GW10-treated eyes, leaving systemic T cell subsets unaffected. In addition, fewer Ly6C+ inflammatory monocyte/macrophages (P = 0.002) and dendritic cells (P = 0.017) crossed the BRB following GW10 treatment. In vitro migration assays confirmed that Th17 cells were selectively suppressed by GW559090 in adhering to endothelial monolayers. Conclusions This α4β1 integrin inhibitor may exert a modulatory effect in EAU progression by selectively blocking Th17 cell migration across the blood-retinal barrier without affecting systemic CD4+ T cell subsets. Local α4β1 integrin-directed inhibition could be clinically relevant in treating a Th17-dominant form of uveitis.
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::71c36b21dd9b2dbdb62eb1c3a7cf8e9dTest
https://doi.org/10.21203/rs.3.rs-65522/v1Test -
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المؤلفون: José Pinto-Fraga, Michael E. Stern, Alberto López-Miguel, Carmen García-Vázquez, Virginia L. Calder, Margarita Calonge, Alberto López-de la Rosa, Itziar Fernández, Amalia Enríquez-de-Salamanca, María J. González-García
المصدر: The Ocular Surface. 16:368-376
مصطلحات موضوعية: Male, 0301 basic medicine, medicine.medical_specialty, medicine.medical_treatment, CCL2, Gastroenterology, CCL5, law.invention, 03 medical and health sciences, 0302 clinical medicine, Double-Blind Method, Randomized controlled trial, law, Internal medicine, medicine, HLA-DR, Humans, Glucocorticoids, business.industry, Clinical study design, Middle Aged, Clinical trial, Ophthalmology, 030104 developmental biology, Cytokine, Tears, 030221 ophthalmology & optometry, Cytokines, Biomarker (medicine), Dry Eye Syndromes, Female, Fluorometholone, business, Biomarkers
الوصف: Purpose To evaluate the effect of 0.1%-fluorometholone (FML) on tear inflammatory molecule levels after 22-days treatment in dry eye disease (DED) patients exposed to an adverse controlled environment (ACE), identifying different biomarkers. Methods Analysis of a double-masked randomized clinical trial. Forty-one DED patients received 4-drops daily of topical FML (FML-group) or polyvinyl-alcohol (PA-group) for 22 days. At day 21, patients were exposed to an ACE. Tear samples were collected at V1 (baseline), V2 (pre-ACE), V3 (post-2-h-ACE) and V4 (24-h post-ACE). Concentrations of 18 molecules (EGF, IFN-γ, TNF-α, IL-1β, IL-1RA, IL-2, IL-4, IL-6, IL-8/CXCL8, IL-10, IL-12, IL-13, IL-17A, IP-10/CXCL10, MCP-1/CCL2, MIP-1α/CCL3, RANTES/CCL5 and MMP-9) were analyzed. Similarities among patients in molecule concentrations at V1 were evaluated. A linear-mixed effect model analyzed the influence of different variables on concentrations changes. Results Multidimensional scaling (MDS) divided patients into two groups based on differences in EGF, IFN-γ, IL-8/CXCL8, RANTES/CCL5, and MMP-9 levels at V1. Groups had different clinical severities based on Schirmer test and conjunctival and corneal staining. IL-1RA, IL-2, and TNF-α were differentially affected by time, depending on treatment. Between V2-V3, there were significant changes in EGF, IL-1RA, IL-2, IL-8/CXCL8, IL-13, IP-10/CXCL10, TNF-α, and MMP-9. The strongest biomarker candidates were IFN-γ, RANTES/CCL5, and MMP-9 as DED severity biomarkers; IL-2 as DED therapeutic biomarker; and EGF as DED activity biomarker. Conclusions This clinical trial design using a controlled environment and the identified tear biomarkers could be useful to objectively select target patients, to define stress response, and to evaluate therapeutic endpoints in clinical trials.
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::869727356b7dabbc09e0c6631d2c07d0Test
https://doi.org/10.1016/j.jtos.2018.05.001Test -
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المؤلفون: Alison J. Hardcastle, John K G Dart, Kathryn P. Burdon, Virginia L. Calder, Nicole Carnt, Dinesh Subedi, Ignatius Pang
المصدر: Investigative Ophthalmology & Visual Science
مصطلحات موضوعية: Adult, Male, 0301 basic medicine, complications, Contact Lenses, Single-nucleotide polymorphism, Disease, Adaptive Immunity, scleritis, Polymorphism, Single Nucleotide, Keratitis, Cornea, Young Adult, 03 medical and health sciences, 0302 clinical medicine, stomatognathic system, innate, medicine, Humans, SNP, Prospective Studies, Inflammation, business.industry, adaptive, Odds ratio, Middle Aged, medicine.disease, Immunity, Innate, Toll-Like Receptor 4, Contact lens, keratitis, 030104 developmental biology, Acanthamoeba Keratitis, Acanthamoeba keratitis, Immunology, 030221 ophthalmology & optometry, Th17 Cells, Female, Disease Susceptibility, Acanthamoeba keratitis (AK), business, Scleritis, genetic susceptibility
الوصف: Purpose: Over a third of patients with Acanthamoeba keratitis (AK) experience severe inflammatory complications (SICs). This study aimed to determine if some contact lens (CL) wearers with AK were predisposed to SICs due to variations in key immune genes. Methods: CL wearers with AK who attended Moorfields Eye Hospital were recruited prospectively between April 2013 and October 2014. SICs were defined as scleritis and/or stromal ring infiltrate. Genomic DNA was processed with an Illumina Low Input Custom Amplicon assay of 58 single nucleotide polymorphism (SNP) targets across 18 genes and tested for association in PLINK. Results: Genomic DNA was obtained and analyzed for 105 cases of AK, 40 (38%) of whom experienced SICs. SNPs in the CXCL8 gene encoding IL-8 was significantly associated with protection from SICs (chr4: rs1126647, odds ratio [OR] = 0.3, P = 0.005, rs2227543, OR = 0.4, P = 0.007, and rs2227307, OR = 0.4, P = 0.02) after adjusting for age, sex, steroids prediagnosis, and herpes simplex keratitis (HSK) misdiagnosis. Two TLR-4 SNPs were associated with increased risk of SICs (chr9: rs4986791 and rs4986790, both OR = 6.9, P = 0.01). Th-17 associated SNPs (chr1: IL-23R rs11209026, chr2: IL-1β rs16944, and chr12: IL-22 rs1179251) were also associated with SICs. Conclusions: The current study identifies biologically relevant genetic variants in patients with AK with SICs; IL-8 is associated with a strong neutrophil response in the cornea in AK, TLR-4 is important in early AK disease, and Th-17 genes are associated with adaptive immune responses to AK in animal models. Genetic screening of patients with AK to predict severity is viable and this would be expected to assist disease management.
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::88297f17e8f49a590f7b6714c531e2c6Test
https://doi.org/10.1167/iovs.62.3.33Test -
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المصدر: The Journal of Immunology. 198:1093-1103
مصطلحات موضوعية: Receptors, CCR6, 0301 basic medicine, Adoptive cell transfer, Chromosomal Proteins, Non-Histone, Immunology, Down-Regulation, chemical and pharmacologic phenomena, Inflammation, Biology, Retina, Autoimmune Diseases, Uveitis, Mice, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, In vivo, medicine, Animals, Immunology and Allergy, Secretion, Orphan receptor, Tumor Necrosis Factor-alpha, Nuclear Proteins, Forkhead Transcription Factors, hemic and immune systems, Nuclear Receptor Subfamily 1, Group F, Member 3, Th1 Cells, In vitro, Bromodomain, 030104 developmental biology, Cancer research, Cytokines, Th17 Cells, Female, medicine.symptom, Transcription Factors, 030215 immunology
الوصف: Experimental autoimmune uveitis (EAU), in which CD4+ Th1 and/or Th17 cells are immunopathogenic, mimics various clinical features of noninfectious uveitis in humans. The impact of bromodomain extraterminal (BET) inhibitors on Th17 cell function was studied in a mouse model of EAU in vivo and in mouse and human Th17 cells in vitro. Two BET inhibitors (GSK151 and JQ1) were able to ameliorate the progression of inflammation in EAU and in mouse CD4+ T cells in vitro, downregulating levels of Th17 cells. Additionally, the uveitogenic capacity of Th17 cells to transfer EAU was abrogated by BET inhibitors in an adoptive transfer model. In human CD4+ T cells, a 5-d exposure to BET inhibitors was accompanied by a significant downregulation of Th17-associated genes IL-17A, IL-22, and retinoic acid–related orphan receptor γt. However, in vitro, the inhibitors had no effect on already polarized Th17 cells. The key finding is that, in response to BET inhibitors, Th17-enriched cultures developed a regulatory phenotype, upregulated FOXP3 expression and IL-10 secretion, and lost pathogenicity in vivo. We conclude that BET targeting of Th17 cells is a potential therapeutic opportunity for a wide range of inflammatory and autoimmune diseases, including uveitis.
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::563d25efcfa6940610ea43d4af1f068fTest
https://doi.org/10.4049/jimmunol.1600735Test -
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المصدر: ResearcherID
مصطلحات موضوعية: Adult, Male, medicine.medical_specialty, Contact Lenses, Enzyme-Linked Immunosorbent Assay, Proinflammatory cytokine, Keratitis, 03 medical and health sciences, 0302 clinical medicine, Ophthalmology, medicine, Humans, Interferon gamma, Eye Infections, Parasitic, Prospective Studies, Eye Proteins, biology, business.industry, Eye infection, Middle Aged, medicine.disease, biology.organism_classification, Acanthamoeba, Contact lens, Acanthamoeba keratitis, Acanthamoeba Keratitis, Case-Control Studies, Tears, 030221 ophthalmology & optometry, Cytokines, Female, business, 030215 immunology, medicine.drug
الوصف: PURPOSE: To determine differences in key tear film cytokines between mild and severe cases of acanthamoeba keratitis (AK) and control contact lens (CL) wearers. METHODS: This was a prospective study of CL wearers with AK attending Moorfields Eye Hospital and control CL wearers from the Institute of Optometry, London. Basal tear specimens were collected by 10-μL capillary tubes (BLAUBRAND intraMark, Wertheim, Germany), and tear protein levels were measured with a multiplex magnetic bead array (Luminex 100; Luminex Corporation, Austin, TX) for cytokines interleukin (IL)-1β, IL-6, IL-8, IL-10, IL-17A, IL-17E, IL-17F, IL-22, and interferon gamma and with enzyme-linked immunosorbent assay (Abcam, Cambridge, United Kingdom) for CXCL2. Severe cases of AK were defined as having active infection for over 12 months and at least 1 severe inflammatory event. RESULTS: One hundred and thirty-two tear samples were collected from a total of 61 cases (15 severe and 46 mild–moderate) and 22 controls. IL-8, part of the Toll-like receptor 4 cytokine cascade, was found to be expressed at a detectable level more often in cases of AK than in control CL wearers (P = 0.003) and in higher concentrations in severe cases than in milder forms of the disease (z = −2.35). IL-22, part of the IL-10 family, and a proinflammatory Th17 cytokine, was detected more often in severe cases than in milder forms of AK (P < 0.02). CONCLUSIONS: Profiling patients with AK during disease shows differences in cytokine levels between severe and milder disease that may inform clinical management. The Toll-like receptor 4 and IL-10/Th17 inflammatory pathways should be included in further investigations of this disease.
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0f72ffd04455c6c82a779a5374ac78adTest
https://pubmed.ncbi.nlm.nih.gov/28489721Test -
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المؤلفون: P W Hellings, Luís Delgado, Pia Allegri, F. Marmouz, Jean Luc Fauquert, Virginia L. Calder, M. Jedrzejczak, Banu Bozkurt, Serge Doan, Carmen Rondon, Andrea Leonardi
المساهمون: Selçuk Üniversitesi
مصطلحات موضوعية: Diagnostic Imaging, medicine.medical_specialty, Eye Diseases, Specific test, diagnosis, Immunology, Immunologic Tests, Diagnostic tools, Severity of Illness Index, Unmet needs, Diagnosis, Differential, 03 medical and health sciences, 0302 clinical medicine, Hypersensitivity, medicine, Humans, Immunology and Allergy, Intensive care medicine, business.industry, Vision Tests, biomarkers, Health Care Costs, Allergens, Ocular allergy, allergic conjunctivitis, Clinical research, 030228 respiratory system, quality of life, ocular allergy, Algorithms, Biomarkers, Quality of Life, Symptom Assessment, Potential biomarkers, Differential, 030221 ophthalmology & optometry, Position paper, Allergists, business
الوصف: WOS: 000412545200005
PubMed: 28387947
Ocular allergy (OA) includes a group of common and less frequent hypersensitivity disorders frequently misdiagnosed and not properly managed. The diagnosis of OA is usually based on clinical history and signs and symptoms, with the support of in vivo and in vitro tests when identification of the specific allergen is required. To date, no specific test is available for the diagnosis of the whole spectrum of the different forms of OA. The lack of recommendations on diagnosis of OA is considered a medical need not only for allergists but also for ophthalmologists. This position paper aims to provide a comprehensive overview of the currently available tools for diagnosing OA to promote a common nomenclature and procedures to be used by different specialists. Questionnaires, sign and symptom grading scales, tests, and potential biomarkers for OA are reviewed. We also identified several unmet needs in the diagnostic tools to generate interest, increase understanding, and inspire further investigations. Tools, recommendations, and algorithms for the diagnosis of OA are proposed for use by both allergists and ophthalmologists. Several unmet needs in the diagnostic tools should be further improved by specific clinical research in OA.
EAACI BoO; ExCom TF budget
Supported by EAACI BoO and ExCom TF budget 2014-16. Final Approval by EAACI ExCom on December 5, 2016. The number of authors exceeds the suggested maximum 8 because of the need for a wide consensus from different European countries and specialties.الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3344a6a6199d944ca0433b43935da5d0Test
https://hdl.handle.net/20.500.12395/34966Test -
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المؤلفون: David Abraham, John Dart, Markella Ponticos, Daniel R. Saban, Julie T. Daniels, Virginia L. Calder, Suryanarayana Rayapureddi, Valerie P J Saw, Sarah D. Ahadome, Jill T. Norman
المصدر: JCI insight. 1(12)
مصطلحات موضوعية: 0301 basic medicine, Adult, Male, Pathology, medicine.medical_specialty, Conjunctiva, Pemphigoid, Benign Mucous Membrane, Retinoic acid, Aldehyde dehydrogenase, Tretinoin, 03 medical and health sciences, chemistry.chemical_compound, Cicatrix, Mice, 0302 clinical medicine, Fibrosis, In vivo, Disulfiram, medicine, Animals, Humans, Cells, Cultured, Aged, Aged, 80 and over, Mucous Membrane, biology, Mucous membrane, General Medicine, Aldehyde Dehydrogenase, Fibroblasts, Middle Aged, medicine.disease, Mice, Inbred C57BL, 030104 developmental biology, medicine.anatomical_structure, chemistry, 030221 ophthalmology & optometry, Cancer research, biology.protein, Female, medicine.drug, Research Article
الوصف: Mucous membrane pemphigoid (MMP) is a systemic mucosal scarring disease, commonly causing blindness, for which there is no antifibrotic therapy. Aldehyde dehydrogenase family 1 (ALDH1) is upregulated in both ocular MMP (OMMP) conjunctiva and cultured fibroblasts. Application of the ALDH metabolite, retinoic acid (RA), to normal human conjunctival fibroblasts in vitro induced a diseased phenotype. Conversely, application of ALDH inhibitors, including disulfiram, to OMMP fibroblasts in vitro restored their functionality to that of normal controls. ALDH1 is also upregulated in the mucosa of the mouse model of scarring allergic eye disease (AED), used here as a surrogate for OMMP, in which topical application of disulfiram decreased fibrosis in vivo. These data suggest that progressive scarring in OMMP results from ALDH/RA fibroblast autoregulation, that the ALDH1 subfamily has a central role in immune-mediated ocular mucosal scarring, and that ALDH inhibition with disulfiram is a potential and readily translatable antifibrotic therapy.
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c8f46e77582c1681e471fbd0d3d5c28aTest
https://pubmed.ncbi.nlm.nih.gov/27699226Test -
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المؤلفون: Priyatham S Mettu, Virginia L. Calder, Nancy J. Reyes, Scott W. Cousins, Daniel R. Saban, Sarah D. Ahadome, Rose Mathew
المصدر: JCI insight. 1(12)
مصطلحات موضوعية: 0301 basic medicine, T cell, Retinoic acid, Aldehyde dehydrogenase, Retinoid X receptor, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, In vivo, Fibrosis, medicine, Fibroblast, biology, business.industry, General Medicine, medicine.disease, eye diseases, 030104 developmental biology, medicine.anatomical_structure, chemistry, Integrin alpha M, 030220 oncology & carcinogenesis, Immunology, biology.protein, business, Research Article
الوصف: Fibrosis is a shared end-stage pathway to lung, liver, and heart failure. In the ocular mucosa (conjunctiva), fibrosis leads to blindness in trachoma, pemphigoid, and allergy. The indirect fibrogenic role of DCs via T cell activation and inflammatory cell recruitment is well documented. However, here we demonstrate that DCs can directly induce fibrosis. In the mouse model of allergic eye disease (AED), classical CD11b+ DCs in the ocular mucosa showed increased activity of aldehyde dehydrogenase (ALDH), the enzyme required for retinoic acid synthesis. In vitro, CD11b+ DC-derived ALDH was associated with 9-cis-retinoic acid ligation to retinoid x receptor (RXR), which induced conjunctival fibroblast activation. In vivo, stimulating RXR led to rapid onset of ocular mucosal fibrosis, whereas inhibiting ALDH activity in DCs or selectively depleting DCs markedly reduced fibrosis. Collectively, these data reveal a profibrotic ALDH-dependent pathway by DCs and uncover a role for DC retinoid metabolism.
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::1cd1cab8743b1ea7cc5346cf3296f318Test
https://pubmed.ncbi.nlm.nih.gov/27595139Test
