Regulatory T cell expansion prevents retinal degeneration in type 2 diabetes
Abstract Background The global incidence of type 2 diabetes (T2D) is rapidly increasing, with retinopathy being its most common complication and a leading cause of preventable blindness. Although the precise mechanisms involved in the development of diabetic retinopathy (DR) are not fully understood...
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BMC
2024-12-01
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| Series: | Journal of Neuroinflammation |
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| Online Access: | https://doi.org/10.1186/s12974-024-03323-0 |
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| author | María Llorián-Salvador Daniel Pérez-Martínez Miao Tang Anna Duarri Marta García-Ramirez Anna Deàs-Just Anna Álvarez-Guaita Lorena Ramos-Pérez Patricia Bogdanov Jose A. Gomez-Sanchez Alan W. Stitt Cristina Hernández Alerie G. de la Fuente Rafael Simó |
| author_facet | María Llorián-Salvador Daniel Pérez-Martínez Miao Tang Anna Duarri Marta García-Ramirez Anna Deàs-Just Anna Álvarez-Guaita Lorena Ramos-Pérez Patricia Bogdanov Jose A. Gomez-Sanchez Alan W. Stitt Cristina Hernández Alerie G. de la Fuente Rafael Simó |
| author_sort | María Llorián-Salvador |
| collection | DOAJ |
| description | Abstract Background The global incidence of type 2 diabetes (T2D) is rapidly increasing, with retinopathy being its most common complication and a leading cause of preventable blindness. Although the precise mechanisms involved in the development of diabetic retinopathy (DR) are not fully understood, defective immunomodulation is a recognized key factor in its pathophysiology. Regulatory T cells (Treg) regulate inflammation and promote regeneration, and while they are known to have important anti-inflammatory and neuroprotective roles in other tissues, including central nervous system, their role in the diabetic retina remains largely unknown. The aim of the present study is to examine the effect of Treg expansion of retinal neurodegeneration, an early event in the pathogenesis of DR. Methods Treg expansion was achieved by co-injecting recombinant mouse IL-2 with anti-IL-2 monoclonal antibody or its isotype in db/db mice as an established model of T2D. Treg expansion was confirmed via flow cytometry in blood, spleen, and retina. Fundus angiography was performed in the days prior to animal sacrifice at 18 weeks. To study the effect of Tregs on retinal neurons, glia and vascular permeability, immunohistochemistry against Cone-Arrestin, PKCα, synaptophysin, ChAT, TH, GFAP, Iba-1, calbindin, Brn3a, RBPMS, isolectin B4, and albumin was used. Retinal VEGF levels were measured with a magnetic bead-based immunoassay, and NLRP3, Casp1, p20 and IL-18 were analyzed by Western Blot in retinal homogenates. Results There was a significant decrease in Treg in db/db mice blood. When this deficiency was corrected in db/db mice by systemic Treg expansion, there was an effective protection against retinal neurodegenerative, gliotic, inflammatory changes and vascular leakage associated with T2D. Importantly, Treg expansion did not impact the T2D phenotype in db/db mice as evaluated by blood glucose, HbA1c and circulating insulin. Conclusion Treg modulation in T2D offers a promising therapeutic approach to prevent early stages of DR. This strategy focuses on reducing neuroinflammation and mitigating the associated neuronal, glial, and vascular degenerative changes characteristic of DR. |
| format | Article |
| id | doaj-art-a9fefcaa0be346cf9fcb589929eda1a9 |
| institution | Kabale University |
| issn | 1742-2094 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | BMC |
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| series | Journal of Neuroinflammation |
| spelling | doaj-art-a9fefcaa0be346cf9fcb589929eda1a92024-12-29T12:39:17ZengBMCJournal of Neuroinflammation1742-20942024-12-0121111510.1186/s12974-024-03323-0Regulatory T cell expansion prevents retinal degeneration in type 2 diabetesMaría Llorián-Salvador0Daniel Pérez-Martínez1Miao Tang2Anna Duarri3Marta García-Ramirez4Anna Deàs-Just5Anna Álvarez-Guaita6Lorena Ramos-Pérez7Patricia Bogdanov8Jose A. Gomez-Sanchez9Alan W. Stitt10Cristina Hernández11Alerie G. de la Fuente12Rafael Simó13Universitat Autònoma de BarcelonaDiabetes and Metabolism Research Unit, Vall d’Hebron Research Institute (VHIR)Department of Psychiatry, Perelman School of Medicine, University of PennsylvaniaOphthalmology Research Group, Vall d’Hebron Research InstitutDiabetes and Metabolism Research Unit, Vall d’Hebron Research Institute (VHIR)Diabetes and Metabolism Research Unit, Vall d’Hebron Research Institute (VHIR)Diabetes and Metabolism Research Unit, Vall d’Hebron Research Institute (VHIR)Diabetes and Metabolism Research Unit, Vall d’Hebron Research Institute (VHIR)Diabetes and Metabolism Research Unit, Vall d’Hebron Research Institute (VHIR)Institute for Health and Biomedical Research of Alicante (ISABIAL)Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University BelfastDiabetes and Metabolism Research Unit, Vall d’Hebron Research Institute (VHIR)Institute for Health and Biomedical Research of Alicante (ISABIAL)Diabetes and Metabolism Research Unit, Vall d’Hebron Research Institute (VHIR)Abstract Background The global incidence of type 2 diabetes (T2D) is rapidly increasing, with retinopathy being its most common complication and a leading cause of preventable blindness. Although the precise mechanisms involved in the development of diabetic retinopathy (DR) are not fully understood, defective immunomodulation is a recognized key factor in its pathophysiology. Regulatory T cells (Treg) regulate inflammation and promote regeneration, and while they are known to have important anti-inflammatory and neuroprotective roles in other tissues, including central nervous system, their role in the diabetic retina remains largely unknown. The aim of the present study is to examine the effect of Treg expansion of retinal neurodegeneration, an early event in the pathogenesis of DR. Methods Treg expansion was achieved by co-injecting recombinant mouse IL-2 with anti-IL-2 monoclonal antibody or its isotype in db/db mice as an established model of T2D. Treg expansion was confirmed via flow cytometry in blood, spleen, and retina. Fundus angiography was performed in the days prior to animal sacrifice at 18 weeks. To study the effect of Tregs on retinal neurons, glia and vascular permeability, immunohistochemistry against Cone-Arrestin, PKCα, synaptophysin, ChAT, TH, GFAP, Iba-1, calbindin, Brn3a, RBPMS, isolectin B4, and albumin was used. Retinal VEGF levels were measured with a magnetic bead-based immunoassay, and NLRP3, Casp1, p20 and IL-18 were analyzed by Western Blot in retinal homogenates. Results There was a significant decrease in Treg in db/db mice blood. When this deficiency was corrected in db/db mice by systemic Treg expansion, there was an effective protection against retinal neurodegenerative, gliotic, inflammatory changes and vascular leakage associated with T2D. Importantly, Treg expansion did not impact the T2D phenotype in db/db mice as evaluated by blood glucose, HbA1c and circulating insulin. Conclusion Treg modulation in T2D offers a promising therapeutic approach to prevent early stages of DR. This strategy focuses on reducing neuroinflammation and mitigating the associated neuronal, glial, and vascular degenerative changes characteristic of DR.https://doi.org/10.1186/s12974-024-03323-0Regulatory T cellsDiabetic retinopathyImmunomodulationRetinaNeurodegenerationInflammation |
| spellingShingle | María Llorián-Salvador Daniel Pérez-Martínez Miao Tang Anna Duarri Marta García-Ramirez Anna Deàs-Just Anna Álvarez-Guaita Lorena Ramos-Pérez Patricia Bogdanov Jose A. Gomez-Sanchez Alan W. Stitt Cristina Hernández Alerie G. de la Fuente Rafael Simó Regulatory T cell expansion prevents retinal degeneration in type 2 diabetes Journal of Neuroinflammation Regulatory T cells Diabetic retinopathy Immunomodulation Retina Neurodegeneration Inflammation |
| title | Regulatory T cell expansion prevents retinal degeneration in type 2 diabetes |
| title_full | Regulatory T cell expansion prevents retinal degeneration in type 2 diabetes |
| title_fullStr | Regulatory T cell expansion prevents retinal degeneration in type 2 diabetes |
| title_full_unstemmed | Regulatory T cell expansion prevents retinal degeneration in type 2 diabetes |
| title_short | Regulatory T cell expansion prevents retinal degeneration in type 2 diabetes |
| title_sort | regulatory t cell expansion prevents retinal degeneration in type 2 diabetes |
| topic | Regulatory T cells Diabetic retinopathy Immunomodulation Retina Neurodegeneration Inflammation |
| url | https://doi.org/10.1186/s12974-024-03323-0 |
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