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Knockout of Sema4D alleviates liver fibrosis by suppressing AOX1 expression
Lifu Wang1, Dinghao Li2, Zifeng Zhu2
1Guangzhou Key Laboratory for Clinical Rapid Diagnosis and Early Warning of Infectious Diseases, KingMed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou 511436, China.
Abstract:
Liver fibrosis can occur in many chronic liver diseases, and no effective treatments are available due to the poorly characterized molecular pathogenesis. Semaphorin 4D (Sema4D) has immune functions and serves important roles in T cell priming. Here, we found that Sema4D was highly expressed in fibrotic liver, and the expression of Sema4D increased with hepatic stellate cells (HSCs) activation. Knockout of Sema4D alleviated liver fibrosis. Mechanistically, knockout of Sema4D alleviated liver fibrosis by suppressing the expression of AOX1 in retinol metabolism. Further investigation demonstrated that retinoic acid receptor α (RARA), an important nuclear receptor of retinoic acid, was reduced by Sema4D knockout during liver fibrogenesis. Sema4D knockout-mediated suppression of liver fibrosis was partly mediated by regulating the balance of Th1, Th2, Th17, and T-bet+Treg cells via inhibiting AOX1/RARA. Thus, targeting Sema4D may hold promise as a potential therapeutic approach for treating liver fibrosis.
Insights
Targeting Semaphorin 4D (Sema4D) shows promise for treating liver fibrosis. Blocking Sema4D reduces liver scarring by regulating retinol metabolism and immune cell balance, offering a new therapeutic avenue.
Area of Science:
- Immunology
- Hepatology
- Molecular Biology
Background:
- Chronic liver diseases often lead to liver fibrosis, a condition with limited effective treatments due to poorly understood molecular mechanisms.
- Semaphorin 4D (Sema4D) is known for its immune functions, particularly in T cell priming, suggesting a potential role in inflammatory liver conditions.
Purpose of the Study:
- To investigate the role of Semaphorin 4D (Sema4D) in the development of liver fibrosis.
- To elucidate the molecular mechanisms by which Sema4D influences liver fibrogenesis and potential therapeutic strategies.
Main Methods:
- Quantitative analysis of Sema4D expression in fibrotic liver tissue.
- Assessment of liver fibrosis severity following Sema4D knockout in a preclinical model.
- Analysis of retinol metabolism pathways, specifically aldehyde oxidase 1 (AOX1) and retinoic acid receptor alpha (RARA) expression.
- Evaluation of immune cell populations, including Th1, Th2, Th17, and T-bet+Treg cells.
Main Results:
- Sema4D expression was significantly elevated in fibrotic livers and correlated with hepatic stellate cell activation.
- Sema4D knockout demonstrably alleviated liver fibrosis.
- Sema4D knockout suppressed liver fibrosis by downregulating AOX1 in retinol metabolism and reducing retinoic acid receptor alpha (RARA) levels.
- The antifibrotic effects of Sema4D knockout were partly attributed to restoring the balance of specific T helper cell subsets.
Conclusions:
- Semaphorin 4D (Sema4D) plays a critical role in promoting liver fibrosis.
- Targeting Sema4D, potentially through AOX1/RARA pathways and immune modulation, represents a promising therapeutic strategy for liver fibrosis.
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