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Myeloid-derived MANF ameliorates ethanol-induced liver injury by enhancing microRNA-223 expression
Huiyuan Xie1, Pingping Zhang2, Shanru Yang3
1Department of Laboratory Medicine, The First Affiliated Hospital of Ningbo University, Ningbo, 315010, Zhejiang, China.
Background:
Myeloid cells play a pivotal role in the pathogenesis of alcoholic liver disease (ALD), yet the mechanisms regulating their function and specific contributions to ALD remain inadequately understood. This study aims to investigate the role of mesencephalic astrocyte-derived neurotrophic factor (MANF) in the development of ALD.
Methods:
Myeloid-specific Manf knockout mice and wild-type controls were fed an ethanol-based diet for 10 days, followed by a single ethanol binge. Hepatic MANF levels, along with the correlation between MANF and inflammatory factors in patients with alcoholic hepatitis, were analyzed using the GSE28619 dataset.
Results:
Our study demonstrated that myeloid MANF expression in the liver was upregulated following chronic-plus-binge ethanol exposure. Deletion of the Manf gene in myeloid cells, including neutrophils, exacerbated ethanol-induced liver injury, steatosis, neutrophil infiltration, and reactive oxygen species production. Mechanistic analysis revealed that MANF promotes neutrophil miR-223 expression, a key anti-inflammatory factor in these cells. MANF enhances miR-223 transcription by increasing the expression of the transcription factor PU.1 via p38 mitogen-activated protein kinase signaling. In addition, hepatic MANF levels were elevated in patients with alcoholic hepatitis and correlated with IL-6, IL-1β, and phagocytic oxidase (phox) p47phoxlevels.
Conclusion:
Myeloid-derived MANF mitigates alcohol-induced liver injury by upregulating the neutrophilic p38-PU.1-miR-223 axis.
Insights
Mesencephalic astrocyte-derived neurotrophic factor (MANF) in myeloid cells protects against alcoholic liver disease by enhancing anti-inflammatory pathways. MANF upregulation mitigates liver injury and inflammation in both mouse models and human patients.
Area of Science:
- Hepatology
- Immunology
- Molecular Biology
Background:
- Myeloid cells are crucial in alcoholic liver disease (ALD) pathogenesis.
- Mechanisms regulating myeloid cell function in ALD are not fully understood.
- Mesencephalic astrocyte-derived neurotrophic factor (MANF) role in ALD requires investigation.
Purpose of the Study:
- To investigate the role of MANF in myeloid cells during ALD development.
- To elucidate the molecular mechanisms by which MANF influences ALD.
Main Methods:
- Utilized myeloid-specific Manf knockout mice and wild-type controls subjected to chronic-plus-binge ethanol exposure.
- Analyzed hepatic MANF levels and correlated MANF with inflammatory factors in alcoholic hepatitis patients using the GSE28619 dataset.
Main Results:
- Myeloid MANF expression increased following ethanol exposure.
- Manf deletion in myeloid cells worsened ethanol-induced liver injury, steatosis, and inflammation.
- MANF promotes neutrophil miR-223 expression via the p38-PU.1 signaling pathway.
- Elevated hepatic MANF levels in alcoholic hepatitis patients correlated with inflammatory markers (IL-6, IL-1β, p47phox).
Conclusions:
- Myeloid-derived MANF plays a protective role in alcoholic liver injury.
- MANF mitigates alcohol-induced liver damage by upregulating the neutrophilic p38-PU.1-miR-223 axis.
