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Macrophage Differentiation and Polarization into an M2-Like Phenotype using a Human Monocyte-Like THP-1 Leukemia Cell Line
Published on: August 2, 2021
GPNMB regulates the differentiation and transformation of monocyte-derived macrophages during MASLD
Junqi Wang1, Huan Wang2, Wenting Yang2
1Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, PR China.; State Key Laboratory of Proteomics, National Center for Protein Sciences, Beijing. Beijing Proteome Research Center, Beijing Institute of Lifeomics, Beijing 102206, PR China; Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha 410008, Hunan, PR China.
Abstract:
Metabolic dysfunction-associated steatotic liver disease (MASLD) is an increasingly concerning global health issue characterized by pronounced hepatic steatosis and liver fibrosis. Hepatic monocyte-derived macrophages (MDMs) are crucial in the pathogenesis of liver fibrosis under MASLD. Nevertheless, the precise functions of MDMs and the underlying mechanisms governing their differentiation remain inadequately elucidated. In this study, we revealed an orchestrator of this process: Glycoprotein Non-Metastatic Melanoma Protein B (GPNMB), one of the characteristic genes of MDMs. Notably, myeloid-specific Gpnmb-knockout contributed to the retention of resident Kupffer cells (KCs) and rerouted monocyte differentiation towards a monocyte-derived macrophage subset that occupies the Kupffer cell niche (MoKC subset, resembling resident KCs), thereby impeding the formation of hepatic lipid-associated macrophages (LAMs). This transition has a profound impact, manifested in significantly reduced steatosis and modestly decreased liver fibrosis in myeloid-specific Gpnmb-knockout mice. In conclusion, our research clarifies the complex interactions between Gpnmb and MDMs and underscores the therapeutic potential of targeting Gpnmb within MDMs to manage MASLD.
Insights
Targeting Glycoprotein Non-Metastatic Melanoma Protein B (GPNMB) in macrophages can reduce liver steatosis and fibrosis in metabolic dysfunction-associated steatotic liver disease (MASLD). This study reveals GPNMB
Area of Science:
- Hepatology
- Immunology
- Molecular Biology
Background:
- Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing health concern characterized by liver fat accumulation and fibrosis.
- Hepatic monocyte-derived macrophages (MDMs) play a key role in MASLD pathogenesis, but their exact functions and differentiation mechanisms are not fully understood.
Purpose of the Study:
- To investigate the role of Glycoprotein Non-Metastatic Melanoma Protein B (GPNMB) in regulating MDM differentiation and its impact on MASLD.
- To explore GPNMB as a potential therapeutic target for MASLD.
Main Methods:
- Generated myeloid-specific Gpnmb-knockout mice.
- Analyzed changes in hepatic macrophage populations (Kupffer cells, monocyte-derived macrophages).
- Assessed liver steatosis and fibrosis levels in knockout mice compared to controls.
Main Results:
- GPNMB deficiency led to the retention of resident Kupffer cells.
- Monocyte differentiation was rerouted towards a Kupffer cell-like subset (MoKC), reducing lipid-associated macrophages (LAMs).
- Myeloid-specific Gpnmb-knockout mice exhibited significantly reduced hepatic steatosis and moderately decreased liver fibrosis.
Conclusions:
- GPNMB is a key regulator of MDM differentiation in the context of MASLD.
- Targeting GPNMB in MDMs offers a promising therapeutic strategy for managing MASLD.
- Understanding GPNMB's role clarifies macrophage dynamics in liver disease progression.
