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

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. Systemic sclerosis is an autoimmune disease causing skin and organ fibrosis. The exact cause is unknown, but inflammation plays a key role. Researchers found a gap in understanding how the GRIM-19 protein affects SSc. Ha Yeon Jeong and colleagues conducted experiments on mice to explore this. The study involved injecting mice with a substance to induce SSc and then treating them with a GRIM-19 plasmid (a small DNA molecule). This experiment aimed to see if GRIM-19 could reduce fibrosis. The study type was an experiment involving 8-week-old male mice. Results showed that overexpression of GRIM-19 reduced skin thickness and inflammation in SSc mice. The researchers concluded that GRIM-19 helps control fibrosis by interacting with mitochondrial STAT3 (a protein involved in cell signaling). Future research could explore GRIM-19 as a potential treatment for SSc. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.