PUBLICATION
Unraveling the role of Ctla-4 in intestinal immune homeostasis through a novel Zebrafish model of inflammatory bowel disease
- Authors
- Qin, L., Hu, C., Zhao, Q., Wang, Y., Fan, D., Lin, A., Xiang, L., Chen, Y., Shao, J.
- ID
- ZDB-PUB-250521-2
- Date
- 2025
- Source
- eLIFE 13: (Journal)
- Registered Authors
- Fan, Dongdong, Lin, Aifu, Shao, Jian-zhong
- Keywords
- Ctla-4 deficiency, immunology, inflammation, inflammatory bowel disease, zebrafish, zebrafish model
- Datasets
- GEO:GSE255304, GEO:GSE211396, GEO:GSE255303
- MeSH Terms
-
- Animals
- Zebrafish Proteins*/genetics
- Zebrafish Proteins*/metabolism
- CTLA-4 Antigen*/genetics
- CTLA-4 Antigen*/immunology
- CTLA-4 Antigen*/metabolism
- Disease Models, Animal
- Intestines*/immunology
- Zebrafish*/genetics
- Zebrafish*/immunology
- Inflammatory Bowel Diseases*/genetics
- Inflammatory Bowel Diseases*/immunology
- Inflammatory Bowel Diseases*/pathology
- Gastrointestinal Microbiome
- Homeostasis*
- PubMed
- 40392591 Full text @ Elife
Citation
Qin, L., Hu, C., Zhao, Q., Wang, Y., Fan, D., Lin, A., Xiang, L., Chen, Y., Shao, J. (2025) Unraveling the role of Ctla-4 in intestinal immune homeostasis through a novel Zebrafish model of inflammatory bowel disease. eLIFE. 13:.
Abstract
Inflammatory bowel disease (IBD) is a chronic and relapsing immune-mediated disorder characterized by intestinal inflammation and epithelial injury. The underlying causes of IBD are not fully understood, but genetic factors have been implicated in genome-wide association studies, including CTLA-4, an essential negative regulator of T cell activation. However, establishing a direct link between CTLA-4 and IBD has been challenging due to the early lethality of CTLA-4 knockout mice. In this study, we identified zebrafish Ctla-4 homolog and investigated its role in maintaining intestinal immune homeostasis by generating a Ctla-4-deficient (ctla-4-/-) zebrafish line. These mutant zebrafish exhibited reduced weight, along with impaired epithelial barrier integrity and lymphocytic infiltration in their intestines. Transcriptomics analysis revealed upregulation of inflammation-related genes, disturbing immune system homeostasis. Moreover, single-cell RNA-sequencing analysis indicated increased Th2 cells and interleukin 13 expression, along with decreased innate lymphoid cells and upregulated proinflammatory cytokines. Additionally, Ctla-4-deficient zebrafish exhibited reduced diversity and an altered composition of the intestinal microbiota. All these phenotypes closely resemble those found in mammalian IBD. Lastly, supplementation with Ctla-4-Ig successfully alleviated intestinal inflammation in these mutants. Altogether, our findings demonstrate the pivotal role of Ctla-4 in maintaining intestinal homeostasis. Additionally, they offer substantial evidence linking CTLA-4 to IBD and establish a novel zebrafish model for investigating both the pathogenesis and potential treatments.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping