Transcriptome Analysis of Porcine PBMCs Reveals the Immune Cascade Response and Gene Ontology Terms Related to Cell Death and Fibrosis in the Progression of Liver Failure

Abstract

Background The key gene sets involved in the progression of acute liver failure (ALF), which has a high mortality rate, remain unclear. This study aims to gain a deeper understanding of the transcriptional response of peripheral blood mononuclear cells (PBMCs) following ALF. Methods ALF was induced by D-galactosamine (D-gal) in a porcine model. PBMCs were separated at time zero (baseline group), 36 h (failure group), and 60 h (dying group) after D-gal injection. Transcriptional profiling was performed using RNA sequencing and analysed using DAVID bioinformatics resources. Results Compared with the baseline group, 816 and 1,845 differentially expressed genes (DEGs) were identified in the failure and dying groups, respectively. A total of five and two gene ontology (GO) term clusters were enriched in 107 GO terms in the failure group and 154 GO terms in the dying group. These GO clusters were primarily immune-related, including genes regulating the inflammasome complex and toll-like receptor signalling pathways. Specifically, GO terms related to cell death, including apoptosis, pyroptosis, and autophagy, and those related to fibrosis, coagulation dysfunction, and hepatic encephalopathy were enriched. Seven Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, cytokine-cytokine receptor interaction, hematopoietic cell lineage, lysosome, rheumatoid arthritis, malaria, and phagosome and pertussis pathways were mapped for DEGs in the failure group. All of these seven KEGG pathways were involved in the 19 KEGG pathways mapped in the dying group. Conclusion We found that the dramatic PBMC transcriptome changes triggered by ALF progression was predominantly related to immune responses. The enriched GO terms related to cell death, fibrosis, and so on, as indicated by PBMC transcriptome analysis, seem to be useful in elucidating potential key gene sets in the progression of ALF. A better understanding of these gene sets might be of preventive or therapeutic interest.

Human liver tissue transcriptomics revealed immunometabolic disturbances and related biomarkers in hepatitis B virus-related acute-on-chronic liver failure

“…immune response (Zhang et al, 2018;Hassan et al, 2022). Furthermore, transcriptomic studies of human peripheral blood mononuclear cells (PBMCs) showed that immunometabolic disorders constitute the core axis of ACLF development (Li et al, 2022).…”

“…New strategies for disease diagnosis and treatment can be developed by decoding genome structure and function, rebuilding gene interaction networks and identifying new biomarkers ( Jiang et al, 2015 ). Previous animal studies based on transcriptional profiling revealed that the progression of liver failure was related to the immune response ( Zhang et al, 2018 ; Hassan et al, 2022 ). Furthermore, transcriptomic studies of human peripheral blood mononuclear cells (PBMCs) showed that immunometabolic disorders constitute the core axis of ACLF development ( Li et al, 2022 ).…”