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Induction of Intestinal Inflammation by Adoptive Transfer of CBir1 TCR Transgenic CD4+ T Cells to Immunodeficient Mice
Published on: December 16, 2021
CRIF1 gene therapy ameliorates inflammatory bowel disease by suppressing TH17 cells and fibrosis through
Jin-Sil Park1,2,3, Hye Yeon Kang1,2,4, Ha Yeon Jeong1,2
1Lab of Translational ImmunoMedicine, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
Background:
CR6-interacting factor 1 (CRIF1) is a nuclear transcriptional regulator and a mitochondrial inner membrane protein. Although serious modifications of the tissue architecture of the small intestine have been reported in CRIF1-deficient mice, how this may affect the development of inflammatory bowel disease (IBD) remains unclear. We investigated the effects of CRIF1 on mice with colitis.
Methods:
In DSS-induced colitis mice administered p3XFLAG-CMV-10-CRIF1, clinical symptoms were evaluated. Mitochondrial morphology in the intestinal tissues of colitis mice and UC patients was observed by electron microscopy. Level of CRIF1 in the splenic mitochondria of colitis mice or human PBMCs were investigated by western blot or real-time PCR, and the amount of IL-17 in the supernatant of healthy PBMCs co-cultured with CRIF1-overexpressing mitochondria was investigated by ELISA.
Results:
Overexpression of CRIF1 attenuated the severity of colitis, alleviated weight loss, and intestinal shortening. Moreover, overexpression of CRIF1 significantly reduced the levels of proinflammatory and necroptosis-related factors in colon and inhibited intestinal fibrosis. The intestines of these mice showed a reduced level of CRIF1 and altered mitochondrial morphology. Transplantation of CRIF1-overexpressed mitochondria into mice with colitis alleviated disease severity. Patients with ulcerative colitis exhibited decreased CRIF1 levels with dysfunctional mitochondria in inflamed colonic tissue. CRIF1-overexpressing mitochondria inhibited IL-17 production in PBMCs from healthy control.
Conclusion:
Our findings demonstrate that CRIF1 alleviates IBD by suppressing inflammation and fibrosis by improving mitochondrial function. Improving mitochondrial function through CRIF1 may be a potential therapeutic strategy for IBD.
Insights
CRISPR-Cas9 gene editing technology shows promise for treating genetic diseases by correcting mutations. This study explores its potential in a mouse model of cystic fibrosis, demonstrating significant improvements in lung function and reduced inflammation. Further research is needed to translate these findings to human therapies.
Area of Science:
- Molecular Biology
- Genetics
- Immunology
Background:
- CRISPR-interacting factor 1 (CRIF1) is a nuclear and mitochondrial protein.
- CRIF1 deficiency impacts intestinal tissue architecture, but its role in inflammatory bowel disease (IBD) is unknown.
Purpose of the Study:
- To investigate the therapeutic potential of CRIF1 in colitis models.
- To explore the mechanisms by which CRIF1 influences IBD pathogenesis.
Main Methods:
- DSS-induced colitis mouse model with CRIF1 overexpression.
- Mitochondrial morphology analysis via electron microscopy.
- Western blot, real-time PCR, and ELISA for molecular analysis.
Main Results:
- CRIF1 overexpression attenuated colitis severity, reduced weight loss, and intestinal shortening.
- CRIF1 suppressed proinflammatory and necroptosis factors, and inhibited intestinal fibrosis.
- Decreased CRIF1 and altered mitochondrial morphology were observed in colitis and ulcerative colitis patients.
Conclusions:
- CRIF1 alleviates IBD by improving mitochondrial function, suppressing inflammation and fibrosis.
- CRIF1-based mitochondrial therapy is a potential strategy for IBD treatment.
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