Cellular and Molecular Mechanisms of Liver Fibrosis in Patients with NAFLD

• Published in: Cancers 2023-05, Vol.15 (11), p.2871
• Main Authors: Sanchez, Jessica I, Parra, Edwin R, Jiao, Jingjing, Solis Soto, Luisa M, Ledesma, Debora A, Saldarriaga, Omar A, Stevenson, Heather L, Beretta, Laura
• Format: Article
• Language: English
• Subjects: Antibodies; Biopsy; Care and treatment; CD11b antigen; CD3 antigen; CD8 antigen; CD90 antigen; Cell density; Chemokines; Cirrhosis; Cloning; Fatty liver; Fibrosis; Foxp3 protein; Gene expression; Genes; Hepatocellular carcinoma; Hepatocytes; Immunofluorescence; Immunological memory; Immunoregulation; Interleukin 8; Kupffer cells; Liver; Liver cancer; Liver cirrhosis; Liver diseases; Lymphocytes T; Macrophages; Medical research; Medicine, Experimental; Memory cells; Molecular modelling; Monocyte chemoattractant protein 1; Patients; Software; Type 2 diabetes
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers15112871

The expression of immune- and cancer-related genes was measured in liver biopsies from 107 NAFLD patients. The strongest difference in overall gene expression was between liver fibrosis stages F3 and F4, with 162 cirrhosis-associated genes identified. Strong correlations with fibrosis progression from F1 to F4 were observed for 91 genes, including CCL21, CCL2, CXCL6, and CCL19. In addition, the expression of 21 genes was associated with fast progression to F3/F4 in an independent group of eight NAFLD patients. These included the four chemokines, SPP1, HAMP, CXCL2, and IL-8. A six-gene signature including SOX9, THY-1, and CD3D had the highest performance detecting the progressors among F1/F2 NAFLD patients. We also characterized immune cell changes using multiplex immunofluorescence platforms. Fibrotic areas were strongly enriched in CD3 T cells compared to CD68 macrophages. While the number of CD68 macrophages increased with fibrosis severity, the increase in CD3 T-cell density was more substantial and progressive from F1 to F4. The strongest correlation with fibrosis progression was observed for CD3 CD45R0 memory T cells, while the most significant increase in density between F1/F2 and F3/F4 was for CD3 CD45RO FOXP3 CD8 and CD3 CD45RO FOXP3 CD8 regulatory T cells. A specific increase in the density of CD68 CD11b Kupffer cells with liver fibrosis progression was also observed.