期刊
IMMUNOLOGY AND CELL BIOLOGY
卷 100, 期 5, 页码 323-337出版社
WILEY
DOI: 10.1111/imcb.12542
关键词
Alternative activation; chloride intracellular channel 3; immune paralysis; liver failure; monocyte-derived macrophages; Kupffer cells
资金
- Guangdong Basic and Applied BasicResearch Foundation [2020A1515010052, 2019A1515011095]
- Natural Fund of Guangdong Province [2016A030313237]
- Guangzhou City Science and Technology Project [201607010064]
- National Science and Technology Major Project [2018ZX10302204]
- National Natural Science Foundation of China [81974004, 81901942]
During the progression of HBV-related liver diseases, the polarization of macrophages gradually shifts from classical activation to alternative activation. The increase in the percentage of alternatively activated macrophages and the suppression of CLIC3 may serve as potential indicators for poor prognosis in patients with HBV-ACLF.
Patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) are characterized by immune paralysis and susceptibility to infections. Macrophages are important mediators of immune responses can be subclassified into two main phenotypes: classically activated and alternatively activated. However, few studies have investigated changes to macrophage polarization in HBV-related liver diseases. Therefore, we investigated the functional status of monocyte-derived macrophages (MDMs) from patients with mild chronic hepatitis B (n = 226), HBV-related compensated cirrhosis (n = 36), HBV-related decompensated cirrhosis (n = 40), HBV-ACLF (n = 62) and healthy controls (n = 10), as well as Kupffer cells (KCs) from patients with HBV-ACLF (n = 3). We found that during the progression of HBV-related liver diseases, the percentage of CD163(+)CD206(+) macrophages increased, while the percentage of CD80(+)human leukocyte antigen-DR+ macrophages decreased significantly. MDMs and KCs mainly exhibited high CD163(+)CD206(+) expression in patients with HBV-ACLF, which predicted poor clinical outcome and higher liver transplantation rate. Transcriptome sequencing analysis revealed that chloride intracellular channel-3 (CLIC3) was reduced in patients with HBV-ACLF, indicating a poor prognosis. To further study the effect of CLIC3 on macrophage polarization, human monocytic THP-1 cell-derived macrophages were used. We found that classical and alternative macrophage activation occurred through nuclear factor kappa B (NF-kappa B) and phosphoinositide 3-kinase/protein kinase B pathways, respectively. CLIC3 suppression inhibited NF-kappa B activation and promoted the alternative activation. In conclusion, macrophage polarization gradually changed from classically activated to alternatively activated as HBV-related liver diseases progressed. Both CLIC3 suppression and increased alternatively activated macrophage percentage were potential indicators of the poor prognosis of patients with HBV-ACLF.
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