mtSTAT3 suppresses rheumatoid arthritis by regulating Th17 and synovial fibroblast inflammatory cell death with IL-17-mediated autophagy dysfunction
Abstract Th17 cells are activated by STAT3 factors in the nucleus, and these factors are correlated with the pathologic progression of rheumatoid arthritis (RA). Recent studies have demonstrated the presence of STAT3 in mitochondria, but its function is unclear. We investigated the novel role of mit...
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Nature Publishing Group
2025-01-01
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| Series: | Experimental and Molecular Medicine |
| Online Access: | https://doi.org/10.1038/s12276-024-01376-y |
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| author | Seon-Yeong Lee Jeonghyeon Moon A Ram Lee Young-Mee Moon Jeong Won Choi Chae Rim Lee Su Been Jeon Hee Su Sohn Jeehee Youn Dongyun Shin Sung-Hwan Park Mi-La Cho |
| author_facet | Seon-Yeong Lee Jeonghyeon Moon A Ram Lee Young-Mee Moon Jeong Won Choi Chae Rim Lee Su Been Jeon Hee Su Sohn Jeehee Youn Dongyun Shin Sung-Hwan Park Mi-La Cho |
| author_sort | Seon-Yeong Lee |
| collection | DOAJ |
| description | Abstract Th17 cells are activated by STAT3 factors in the nucleus, and these factors are correlated with the pathologic progression of rheumatoid arthritis (RA). Recent studies have demonstrated the presence of STAT3 in mitochondria, but its function is unclear. We investigated the novel role of mitochondrial STAT3 (mitoSTAT3) in Th17 cells and fibroblast-like synoviocytes (FLSs) and analyzed the correlation of mitoSTAT3 with RA. We used a collagen-induced arthritis (CIA) mouse model to determine the effect of mitochondrial STAT3. We observed changes in the RA mouse model via the use of a mitochondrial STAT3-inducing vector and inhibitor. We observed the accumulation of abnormal autophagosomes, increased inflammatory cell death signaling, and decreased mitoSTAT3 activity in FLSs from both patients with RA and patients with IL-17-treated FLSs. We first discovered that IL-17 increased the accumulation of abnormal autophagosomes and the expression of inflammatory cell death factors in synovial fibroblasts and decreased mitoSTAT3 activation. In a mouse model of CIA, arthritis and joint inflammation were decreased by injection vectors that induced mitoSTAT3 overexpression. The abnormal accumulation of autophagosomes and the expression of inflammatory cell death factors were also decreased in these mice. In mouse and human immune cells, ZnSO4, an inducer of mitochondrial STAT3, decreases the production of reactive oxygen species, the IL-17 concentration, and differentiation into Th17 cells. However, mitoSTAT3 blockade accelerated the development of arthritis, inflammatory cell death, and abnormal autophagosome/autophagolysosome formation. Therefore, this study suggests a novel inhibitory mechanism of RA using mitoSTAT3 via the regulation of autophagy, Th17 differentiation, and inflammatory cell death. |
| format | Article |
| id | doaj-art-6e55f925ba484403a90f268b3ad9df17 |
| institution | Kabale University |
| issn | 2092-6413 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Experimental and Molecular Medicine |
| spelling | doaj-art-6e55f925ba484403a90f268b3ad9df172025-02-09T12:14:16ZengNature Publishing GroupExperimental and Molecular Medicine2092-64132025-01-0157122123410.1038/s12276-024-01376-ymtSTAT3 suppresses rheumatoid arthritis by regulating Th17 and synovial fibroblast inflammatory cell death with IL-17-mediated autophagy dysfunctionSeon-Yeong Lee0Jeonghyeon Moon1A Ram Lee2Young-Mee Moon3Jeong Won Choi4Chae Rim Lee5Su Been Jeon6Hee Su Sohn7Jeehee Youn8Dongyun Shin9Sung-Hwan Park10Mi-La Cho11Lab of Translational ImmunoMedicine, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of KoreaDepartments of Neurology and Immunobiology, Yale School of MedicineLab of Translational ImmunoMedicine, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of KoreaLab of Translational ImmunoMedicine, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of KoreaLab of Translational ImmunoMedicine, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of KoreaLab of Translational ImmunoMedicine, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of KoreaLab of Translational ImmunoMedicine, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of KoreaDivision of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women’s HospitalLaboratory of Autoimmunology, Department of Anatomy and Cell Biology, Hanyang University College of MedicineCollege of Pharmacy, Gachon UniversityDivison of Rheumatology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of KoreaLab of Translational ImmunoMedicine, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of KoreaAbstract Th17 cells are activated by STAT3 factors in the nucleus, and these factors are correlated with the pathologic progression of rheumatoid arthritis (RA). Recent studies have demonstrated the presence of STAT3 in mitochondria, but its function is unclear. We investigated the novel role of mitochondrial STAT3 (mitoSTAT3) in Th17 cells and fibroblast-like synoviocytes (FLSs) and analyzed the correlation of mitoSTAT3 with RA. We used a collagen-induced arthritis (CIA) mouse model to determine the effect of mitochondrial STAT3. We observed changes in the RA mouse model via the use of a mitochondrial STAT3-inducing vector and inhibitor. We observed the accumulation of abnormal autophagosomes, increased inflammatory cell death signaling, and decreased mitoSTAT3 activity in FLSs from both patients with RA and patients with IL-17-treated FLSs. We first discovered that IL-17 increased the accumulation of abnormal autophagosomes and the expression of inflammatory cell death factors in synovial fibroblasts and decreased mitoSTAT3 activation. In a mouse model of CIA, arthritis and joint inflammation were decreased by injection vectors that induced mitoSTAT3 overexpression. The abnormal accumulation of autophagosomes and the expression of inflammatory cell death factors were also decreased in these mice. In mouse and human immune cells, ZnSO4, an inducer of mitochondrial STAT3, decreases the production of reactive oxygen species, the IL-17 concentration, and differentiation into Th17 cells. However, mitoSTAT3 blockade accelerated the development of arthritis, inflammatory cell death, and abnormal autophagosome/autophagolysosome formation. Therefore, this study suggests a novel inhibitory mechanism of RA using mitoSTAT3 via the regulation of autophagy, Th17 differentiation, and inflammatory cell death.https://doi.org/10.1038/s12276-024-01376-y |
| spellingShingle | Seon-Yeong Lee Jeonghyeon Moon A Ram Lee Young-Mee Moon Jeong Won Choi Chae Rim Lee Su Been Jeon Hee Su Sohn Jeehee Youn Dongyun Shin Sung-Hwan Park Mi-La Cho mtSTAT3 suppresses rheumatoid arthritis by regulating Th17 and synovial fibroblast inflammatory cell death with IL-17-mediated autophagy dysfunction Experimental and Molecular Medicine |
| title | mtSTAT3 suppresses rheumatoid arthritis by regulating Th17 and synovial fibroblast inflammatory cell death with IL-17-mediated autophagy dysfunction |
| title_full | mtSTAT3 suppresses rheumatoid arthritis by regulating Th17 and synovial fibroblast inflammatory cell death with IL-17-mediated autophagy dysfunction |
| title_fullStr | mtSTAT3 suppresses rheumatoid arthritis by regulating Th17 and synovial fibroblast inflammatory cell death with IL-17-mediated autophagy dysfunction |
| title_full_unstemmed | mtSTAT3 suppresses rheumatoid arthritis by regulating Th17 and synovial fibroblast inflammatory cell death with IL-17-mediated autophagy dysfunction |
| title_short | mtSTAT3 suppresses rheumatoid arthritis by regulating Th17 and synovial fibroblast inflammatory cell death with IL-17-mediated autophagy dysfunction |
| title_sort | mtstat3 suppresses rheumatoid arthritis by regulating th17 and synovial fibroblast inflammatory cell death with il 17 mediated autophagy dysfunction |
| url | https://doi.org/10.1038/s12276-024-01376-y |
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