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IL-6 induces Treg dysfunction in desiccating stress-induced dry eye disease.
Ortiz, Gustavo; Blanco, Tomas; Singh, Rohan Bir; Kahale, Francesca; Wang, Shudan; Chen, Yihe; Dana, Reza.
Afiliación
  • Ortiz G; Laboratory of Ocular Immunology, Transplantation, and Regeneration, Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.
  • Blanco T; Laboratory of Ocular Immunology, Transplantation, and Regeneration, Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.
  • Singh RB; Laboratory of Ocular Immunology, Transplantation, and Regeneration, Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.
  • Kahale F; Laboratory of Ocular Immunology, Transplantation, and Regeneration, Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.
  • Wang S; Laboratory of Ocular Immunology, Transplantation, and Regeneration, Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.
  • Chen Y; Laboratory of Ocular Immunology, Transplantation, and Regeneration, Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.
  • Dana R; Laboratory of Ocular Immunology, Transplantation, and Regeneration, Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA. Electronic address: Reza_Dana@meei.harvard.edu.
Exp Eye Res ; 246: 110006, 2024 Sep.
Article en En | MEDLINE | ID: mdl-39009059
ABSTRACT
Regulatory T cells (Tregs) play a critical role in maintaining immune homeostasis, and their dysfunction is implicated in the pathogenesis of various autoimmune disorders, including dry eye disease (DED). Treg dysfunction in DED allows T-helper cell 17 (Th17) mediated chronic inflammation at the ocular surface. In this study, the factors causing Treg dysfunction in DED were investigated. We observed reduced expression of Treg functional markers - FoxP3, CD25, and CTLA-4 in the cells isolated from DED mice (DED Tregs). Additionally, DED Tregs showed increased expression levels of receptors for pro-inflammatory cytokine receptors, namely IL-6R, IL-17RA, and IL-23R. An increased expression level of pro-inflammatory cytokine receptors was observed on exposing Tregs isolated from naïve mice (NTregs) to IL-6 or IL-17, but not IL-23, with a concomitant downregulation of FoxP3, CD25, and CTLA-4 in these cells. Furthermore, among these cytokines, IL-6 induced the most pronounced loss of Treg mediated suppression of Th17 proliferation and IL-10 secretion. In vitro and in vivo blockade of IL-6 effectively restored function in DED Tregs, leading to enhanced suppressive function against proliferating Th17 cells and ameliorating disease severity. In conclusion, this study provides insights into mechanisms of Treg dysregulation in DED, specifically delineating the effect of Th17-associated cytokines, with IL-6 emerging as the critical factor inducing Treg dysfunctionality. These findings highlight the potential for developing novel therapeutic interventions for DED through restoration of immunosuppressive function of Tregs.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Síndromes de Ojo Seco / Interleucina-6 / Linfocitos T Reguladores / Modelos Animales de Enfermedad / Factores de Transcripción Forkhead / Ratones Endogámicos C57BL Límite: Animals Idioma: En Revista: Exp Eye Res Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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XML
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Síndromes de Ojo Seco / Interleucina-6 / Linfocitos T Reguladores / Modelos Animales de Enfermedad / Factores de Transcripción Forkhead / Ratones Endogámicos C57BL Límite: Animals Idioma: En Revista: Exp Eye Res Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido