Mesenchymal stem cell-derived extracellular vesicles subvert Th17 cells by destabilizing RORγt through posttranslational modification
Abstract Mesenchymal stem cell (MSC)-derived small extracellular vesicles (MSC-sEVs) are known to exert immunosuppressive functions. This study showed that MSC-sEVs specifically convert T helper 17 (Th17) cells into IL-17 low-producer (ex-Th17) cells by degrading RAR-related orphan receptor γt (RORγ...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2023-03-01
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| Series: | Experimental and Molecular Medicine |
| Online Access: | https://doi.org/10.1038/s12276-023-00949-7 |
| _version_ | 1827956977327669248 |
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| author | Sunyoung Jung Sunho Lee Hyun Je Kim Sueon Kim Ji Hwan Moon Hyunwoo Chung Seong-Jun Kang Chung-Gyu Park |
| author_facet | Sunyoung Jung Sunho Lee Hyun Je Kim Sueon Kim Ji Hwan Moon Hyunwoo Chung Seong-Jun Kang Chung-Gyu Park |
| author_sort | Sunyoung Jung |
| collection | DOAJ |
| description | Abstract Mesenchymal stem cell (MSC)-derived small extracellular vesicles (MSC-sEVs) are known to exert immunosuppressive functions. This study showed that MSC-sEVs specifically convert T helper 17 (Th17) cells into IL-17 low-producer (ex-Th17) cells by degrading RAR-related orphan receptor γt (RORγt) at the protein level. In experimental autoimmune encephalomyelitis (EAE)-induced mice, treatment with MSC-sEVs was found to not only ameliorate clinical symptoms but also to reduce the number of Th17 cells in draining lymph nodes and the central nervous system. MSC-sEVs were found to destabilize RORγt by K63 deubiquitination and deacetylation, which was attributed to the EP300-interacting inhibitor of differentiation 3 (Eid3) contained in the MSC-sEVs. Small extracellular vesicles isolated from the Eid3 knockdown MSCs by Eid3-shRNA failed to downregulate RORγt. Moreover, forced expression of Eid3 by gene transfection was found to significantly decrease the protein level of RORγt in Th17 cells. Altogether, this study reveals the novel immunosuppressive mechanisms of MSC-sEVs, which suggests the feasibility of MSC-sEVs as an attractive therapeutic tool for curing Th17-mediated inflammatory diseases. |
| first_indexed | 2024-04-09T15:11:53Z |
| format | Article |
| id | doaj.art-787e543b53354489b9d8a28a17b5418b |
| institution | Directory Open Access Journal |
| issn | 2092-6413 |
| language | English |
| last_indexed | 2024-04-09T15:11:53Z |
| publishDate | 2023-03-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Experimental and Molecular Medicine |
| spelling | doaj.art-787e543b53354489b9d8a28a17b5418b2023-04-30T11:08:34ZengNature Publishing GroupExperimental and Molecular Medicine2092-64132023-03-0155366567910.1038/s12276-023-00949-7Mesenchymal stem cell-derived extracellular vesicles subvert Th17 cells by destabilizing RORγt through posttranslational modificationSunyoung Jung0Sunho Lee1Hyun Je Kim2Sueon Kim3Ji Hwan Moon4Hyunwoo Chung5Seong-Jun Kang6Chung-Gyu Park7Department of Microbiology and Immunology, Seoul National University College of MedicineDepartment of Microbiology and Immunology, Seoul National University College of MedicineDepartment of Biomedical Sciences, Seoul National University College of MedicineDepartment of Microbiology and Immunology, Seoul National University College of MedicineSamsung Genome Institute, Samsung Medical CenterDepartment of Microbiology and Immunology, Seoul National University College of MedicineDepartment of Microbiology and Immunology, Seoul National University College of MedicineDepartment of Microbiology and Immunology, Seoul National University College of MedicineAbstract Mesenchymal stem cell (MSC)-derived small extracellular vesicles (MSC-sEVs) are known to exert immunosuppressive functions. This study showed that MSC-sEVs specifically convert T helper 17 (Th17) cells into IL-17 low-producer (ex-Th17) cells by degrading RAR-related orphan receptor γt (RORγt) at the protein level. In experimental autoimmune encephalomyelitis (EAE)-induced mice, treatment with MSC-sEVs was found to not only ameliorate clinical symptoms but also to reduce the number of Th17 cells in draining lymph nodes and the central nervous system. MSC-sEVs were found to destabilize RORγt by K63 deubiquitination and deacetylation, which was attributed to the EP300-interacting inhibitor of differentiation 3 (Eid3) contained in the MSC-sEVs. Small extracellular vesicles isolated from the Eid3 knockdown MSCs by Eid3-shRNA failed to downregulate RORγt. Moreover, forced expression of Eid3 by gene transfection was found to significantly decrease the protein level of RORγt in Th17 cells. Altogether, this study reveals the novel immunosuppressive mechanisms of MSC-sEVs, which suggests the feasibility of MSC-sEVs as an attractive therapeutic tool for curing Th17-mediated inflammatory diseases.https://doi.org/10.1038/s12276-023-00949-7 |
| spellingShingle | Sunyoung Jung Sunho Lee Hyun Je Kim Sueon Kim Ji Hwan Moon Hyunwoo Chung Seong-Jun Kang Chung-Gyu Park Mesenchymal stem cell-derived extracellular vesicles subvert Th17 cells by destabilizing RORγt through posttranslational modification Experimental and Molecular Medicine |
| title | Mesenchymal stem cell-derived extracellular vesicles subvert Th17 cells by destabilizing RORγt through posttranslational modification |
| title_full | Mesenchymal stem cell-derived extracellular vesicles subvert Th17 cells by destabilizing RORγt through posttranslational modification |
| title_fullStr | Mesenchymal stem cell-derived extracellular vesicles subvert Th17 cells by destabilizing RORγt through posttranslational modification |
| title_full_unstemmed | Mesenchymal stem cell-derived extracellular vesicles subvert Th17 cells by destabilizing RORγt through posttranslational modification |
| title_short | Mesenchymal stem cell-derived extracellular vesicles subvert Th17 cells by destabilizing RORγt through posttranslational modification |
| title_sort | mesenchymal stem cell derived extracellular vesicles subvert th17 cells by destabilizing rorγt through posttranslational modification |
| url | https://doi.org/10.1038/s12276-023-00949-7 |
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