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Deficiency of IL-27 Signaling Exacerbates Experimental Autoimmune Uveitis with Elevated Uveitogenic Th1 and Th17 Responses.
- Source :
-
International journal of molecular sciences [Int J Mol Sci] 2021 Jul 14; Vol. 22 (14). Date of Electronic Publication: 2021 Jul 14. - Publication Year :
- 2021
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Abstract
- Human uveitis is an autoimmune disease of the central nervous system that is characterized by ocular inflammation with the involvement of uveitogenic Th1 and Th17 responses. In experimental autoimmune uveitis (EAU), the animal model for human uveitis, both responses are proven to be critical in disease development. Therefore, targeting both Th1 and Th17 cells has therapeutic implication for disease resolution. IL-27 is a multifunctional cytokine that can either promote or inhibit T cell responses and is implicated in both autoimmune and infectious diseases. The aim of this study is to characterize the role of IL-27/IL-27R signaling in regulating uveitogenic Th1/Th17 responses in EAU. By immunizing IL-27Rα <superscript>-/-</superscript> mice and their wild-type (WT) littermates for EAU, we demonstrated that IL-27 signaling deficiency exacerbated EAU with severe ocular inflammation and impairment of visual function. Furthermore, there was a significant increase in the eye-infiltrating Th1 and Th17 cells in IL-27Rα <superscript>-/-</superscript> EAU mice compared to WT. Their retinal antigen-specific Th1 and Th17 responses were also significantly increased, as represented by the elevation of their signature cytokines, IFN-γ and IL-17A, respectively. We also observed the upregulation of another pathogenic cytokine, granulocyte-macrophage colony-stimulating factor (GM-CSF), from effector T cells in IL-27Rα <superscript>-/-</superscript> EAU mice. Mechanistic studies confirmed that IL-27 inhibited GM-CSF production from Th17 cells. In addition, the induction of IL-10 producing type 1 regulatory T (Tr1) cells was impaired in IL-27Rα <superscript>-/-</superscript> EAU mice. These results identified that IL-27 signaling plays a suppressive role in EAU by regulating multiple CD4 <superscript>+</superscript> cell subsets, including the effector Th1 and Th17 cells and the regulatory Tr1 cells. Our findings provide new insights for therapeutic potential in controlling uveitis by enhancing IL-27 signaling.
- Subjects :
- Animals
Autoimmune Diseases etiology
Autoimmune Diseases metabolism
Cell Differentiation
Cytokines metabolism
Disease Models, Animal
Mice
Mice, Inbred C57BL
Mice, Knockout
Uveitis etiology
Uveitis metabolism
Autoimmune Diseases pathology
CD4-Positive T-Lymphocytes immunology
Interleukin-27 metabolism
Receptors, Interleukin physiology
Th1 Cells immunology
Th17 Cells immunology
Uveitis pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1422-0067
- Volume :
- 22
- Issue :
- 14
- Database :
- MEDLINE
- Journal :
- International journal of molecular sciences
- Publication Type :
- Academic Journal
- Accession number :
- 34299138
- Full Text :
- https://doi.org/10.3390/ijms22147517