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Published on: January 7, 2019
Hic-5 deficiency attenuates MAFLD by inhibiting neutrophils migration via the CXCL1-CXCR2 axis
Bingyu Ren1, Han Li1, Shenglu Liu1
1Department of General Surgery (Hepatopancreatobiliary Surgery), Department of Biliary-Pancreatic Center, The Affiliated Hospital of Southwest Medical University, 25 Taiping Street, Jiangyang District, Luzhou City, 646000, Sichuan Province, China.
Background And Aims:
Inflammatory cell infiltration in the liver is a hallmark of metabolic dysfunction-associated fatty liver disease (MAFLD). However, the pathological events that trigger the infiltration of inflammatory cells to mediate MAFLD pathogenesis remains poorly understood. This study aims to investigate the function and mechanism of Hic-5 on hepatic inflammation of MAFLD.
Methods:
MAFLD animal models were fed a methionine- and choline-deficient (MCD) diet in Hic-5 knockout mice. Liver tissues were analyzed by immunohistochemical staining, immunofluorescence and flow cytometry, with a particular focus on the impact on the immune microenvironment.
Results:
Hic-5 deficiency alleviates the severity of MAFLD, particularly the inflammation response. Gain- and loss-of-function experiments revealed that Hic-5 deficiency results in decreased neutrophil proliferation and increased apoptosis, as well as impaired migration. Conversely, Hic-5 overexpression had the opposite effects. This study confirmed that METTL3-mediated methylation of m6A stabilizes Hic-5 mRNA and promotes its expression, which in turn regulates the infiltration of neutrophils by the CXCL1-CXCR2 axis.
Conclusions:
The study reveals the role of Hic-5 in regulating neutrophils and indicates that it may be a potential therapeutic target for MAFLD.
Insights
Hic-5 deficiency reduces liver inflammation in metabolic dysfunction-associated fatty liver disease (MAFLD) by controlling neutrophil activity. This suggests Hic-5 is a potential therapeutic target for MAFLD.
Area of Science:
- Hepatology
- Immunology
- Molecular Biology
Background:
- Inflammatory cell infiltration is key in metabolic dysfunction-associated fatty liver disease (MAFLD).
- The precise triggers for this inflammation in MAFLD pathogenesis are not fully understood.
- Investigating novel factors like Hic-5 is crucial for understanding MAFLD.
Purpose of the Study:
- To elucidate the function and mechanism of Hic-5 in hepatic inflammation within MAFLD.
- To determine Hic-5's role in regulating immune cell infiltration in the liver.
Main Methods:
- Utilized a methionine- and choline-deficient (MCD) diet model in Hic-5 knockout mice.
- Analyzed liver tissues using immunohistochemistry, immunofluorescence, and flow cytometry.
- Focused on the impact of Hic-5 on the hepatic immune microenvironment.
Main Results:
- Hic-5 deficiency significantly reduced MAFLD severity and hepatic inflammation.
- Loss of Hic-5 decreased neutrophil proliferation and migration while increasing apoptosis.
- METTL3-mediated m6A methylation stabilizes Hic-5 mRNA, regulating neutrophil infiltration via the CXCL1-CXCR2 axis.
Conclusions:
- Hic-5 plays a critical role in regulating neutrophil behavior in MAFLD.
- Targeting Hic-5 presents a potential therapeutic strategy for MAFLD treatment.
