2. Academic Validation
  3. GRIM-19-mediated induction of mitochondrial STAT3 alleviates systemic sclerosis by inhibiting fibrosis and Th2/Th17 cells

GRIM-19-mediated induction of mitochondrial STAT3 alleviates systemic sclerosis by inhibiting fibrosis and Th2/Th17 cells

  • Exp Mol Med. 2024 Dec;56(12):2739-2746. doi: 10.1038/s12276-024-01366-0.
Ha Yeon Jeong # 1 2,  Jin-Sil Park # 1 2 3,  Jeong Won Choi 1 2,  Kun Hee Lee 1 2,  Seung Cheon Yang 1,  Hye Yeon Kang 1 2 4,  Sang Hee Cho 1 2 4,  Seon-Yeong Lee 1 2,  A Ram Lee 1 2,  Youngjae Park 3 5,  Sung-Hwan Park 6 7,  Mi-La Cho 8 9 10
Affiliations

Affiliations

  • 1 Lab of Translational ImmunoMedicine, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, 06591, South Korea.
  • 2 Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, 06591, South Korea.
  • 3 The Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, 06591, South Korea.
  • 4 Department of Medical Sciences, Graduate School of The Catholic University of Korea, Seoul, 06591, South Korea.
  • 5 Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, 06591, South Korea.
  • 6 The Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, 06591, South Korea. rapark@catholic.ac.kr.
  • 7 Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, 06591, South Korea. rapark@catholic.ac.kr.
  • 8 Lab of Translational ImmunoMedicine, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, 06591, South Korea. iammila@catholic.ac.kr.
  • 9 Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, 06591, South Korea. iammila@catholic.ac.kr.
  • 10 Department of Medical Sciences, Graduate School of The Catholic University of Korea, Seoul, 06591, South Korea. iammila@catholic.ac.kr.
  • # Contributed equally.
PMID: 39643607 DOI: 10.1038/s12276-024-01366-0
Abstract

The gene associated with the retinoid-IFN-induced mortality-19 (GRIM-19) protein is a regulator of a cell death regulatory protein that inhibits STAT3, which is a critical transcription factor for interleukin (IL)-17-producing T (Th17) cells and a key integrator of extracellular matrix accumulation in systemic sclerosis (SSc). This protein is also a component of mitochondrial complex I, where it directly binds to STAT3 and recruits STAT3 to the mitochondria via the mitochondrial importer Tom20. In this study, the role of GRIM19 and its relationship with STAT3 in SSc development was investigated using a murine model of SSc. We observed a decrease in the level of GRIM-19 in the lesional skin of mice with bleomycin-induced SSc, which was negatively correlated with the level of STAT3. Overexpression of GRIM-19 reduced dermal thickness and fibrosis and the frequency of Th2 and Th17 cells in SSc mice. Mitophagic dysfunction promoted fibrosis in mice lacking PINK1, which is a Mitophagy inducer. In an in vitro system, the overexpression of GRIM-19 increased the level of mitochondrial STAT3 (mitoSTAT3), induced Mitophagy, and alleviated fibrosis progression. MitoSTAT3 overexpression hindered the development of bleomycin-induced SSc by reducing fibrosis. These results suggest that GRIM-19 is an effective therapeutic target for alleviating the development of SSc by increasing Mitophagy.

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