CLIC3 Suppression-Mediated Macrophage Polarization Predicts the Prognosis of HBV-Related Acute-on-Chronic Liver Failure

Background: Patients with HBV-related acute-on-chronic liver failure (HBV-ACLF) are characterized by immune paralysis and susceptibility to infections. Macrophages are reported to polarize to proinflammatory or anti-inflammatory functional states in different morbid states. However, the molecular mechanisms of macrophage polarization in the disease progression of HBV-ACLF have not yet been elucidated. Aims: To investigate the dynamic macrophage polarization changes in different stages of HBV-related liver disease and explore the potential mechanism of macrophage polarization during HBV-ACLF. Methods: The functional status of peripheral blood mononuclear cells derived from macrophages from patients with mild chronic hepatitis B, HBV-related compensated liver cirrhosis, HBV-related decompensated liver cirrhosis, HBV-ACLF and healthy controls was determined. A transcriptome sequencing analysis was performed to investigate the pathways involved in macrophage polarization in HBV-ACLF. The chloride intracellular channel-3 (CLIC3) gene expression was suppressed in the human monocytic THP-1-derived macrophages to study its role in macrophage polarization. Results: Macrophages exhibited different functional statuses in different stages of HBV-related liver disease. Macrophages were mainly exhibiting an anti-inflammatory phenotype and functional characteristics in patients with HBV-ACLF, which was predictive of a poor clinical outcome. The expression of CLIC3, which is involved in immunological diseases, was reduced in HBV-ACLF patients, indicating a poor prognosis. In addition, CLIC3 could regulate proinflammatory macrophage polarization through the NF-κB and Akt pathways. Conclusion: Macrophage polarization changes dynamically in HBV-related liver diseases. CLIC3 suppression-mediated anti-inflammatory macrophage polarization plays an important role in the progression of HBV-ACLF, and CLIC3 expression is a potential indicator of the prognosis of HBV-ACLF patients. Funding Statement: Supported by the Guangzhou City Science and Technology Project (No. 201607010064), the Natural Fund of Guangdong Province (No. 2016A030313237), the National Science and Technology Major Project (2018ZX10302204) and The National Natural Science Foundation of China (81672701). Declaration of Interests: The authors declare no conflicts of interest. Ethics Approval Statement: This study was approved by the Third Affiliated Hospital of Sun Yat-Sen University Ethics Committee ([2018]02-432-01). If patients were unable to provide consent, informed consent was obtained from the next of kin.