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Mesenchymal stem cell-derived extracellular vesicles subvert Th17 cells by destabilizing RORγt through posttranslational modification

Jung Sunyoung|Park Chung-Gyu|Kim Hyun Je|Lee Sunho|Chung Hyunwoo|Kang Seong-Jun|Kim Sueon|Moon Ji Hwan
생화학분자생물학회 (Korean Society Of Biochemistry And Molecular Biology)|2023.12|Experimental and Molecular Medicine|제55권 |pp. 665-679|DOI 10.1038/s12276-023-00949-7

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주제분류생화학

초록

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.

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.

참고문헌 (58)

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관련 논문AI추천

Erratum : Mesenchymal stem cell-derived extracellular vesicles subvert Th17 cells by destabilizing RORγt through posttranslational modificationChung Hyunwoo, Jung Sunyoung, Kang Seong-Jun, Kim Hyun Je, Kim Sueon, Lee Sunho, Moon Ji Hwan, Park Chung-Gyu생화학분자생물학회 · Experimental and Molecular Medicine2023 · 제55권 Preclinical Efficacy and Mechanisms of Mesenchymal Stem Cells in Animal Models of Autoimmune Diseases김영수, 이홍경, 한상배, In Sung Chung, Jin Tae HONG, Ju Young Kim, Mi Jeong Park, Sang Hee Lim, Yong Guk Kim, Yunsoo Park대한면역학회 · Immune Network2014 · 제14권 제2호Immunomodulatory effect of mesenchymal stem cells and mesenchymal stem-cell-derived exosomes for COVID-19 treatment이윤주, 임경민, 조쌍구, 아브달아메드, Arthi Kirubhakaran, Balachandar Vellingiri, Iyer Mahalaxmi, Jong Yub An, Kaavya Jayaramayya, Mohana Devi Subramaniam, Neethu Raj, Se Jong Kim, Yujin Choi생화학분자생물학회 · BMB Reports2020 · 제53권 제8호Recent Advances in Cell Therapeutics for Systemic Autoimmune Diseases곽승기, 박영재대한면역학회 · Immune Network2022 · 제22권 제1호Th17 cell pathogenicity in autoimmune diseaseCiofani Maria, Park Eunchong생화학분자생물학회 · Experimental and Molecular Medicine2025 · 제57권 IL-17A-Producing Foxp3+ Regulatory T Cells and Human Diseases곽정은, 신의철, 정민경대한면역학회 · Immune Network2017 · 제17권 제5호

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