Transcriptome Sequencing Unveils Immune Heterogeneity between Systemic Immune Response and the Liver Immune Microenvironment along HBV-ACLF Development

Abstract

Abstract Background The COSSH-ACLF criteria provides a grading system feasible for Chinese ACLF population featured with HBV infection background. However, insufficient mechanical foundation is available for the grading system. In the present study, we aimed to explore the status of the liver microenvironment as well as circulating immune components of HBV-ACLF patients and to establish metabolic biomarkers representing immune phenotypes corresponding to COSSH-ACLF grades. Methods Transcriptome sequencing on liver-infiltrated CD45+ immune cells and PBMCs from HBV-ACLF patients were applied. ACLF mouse models were constructed with chronic CCl4 administration combined with instant K.P. induction. Results We revealed the most prominent turbulence in immune and metabolism modules along the development of the disease. Immune profiling analysis revealed a generally exhausted liver immune microenvironment. Significant immune heterogeneity of the liver microenvironment was observed compared with immune response in circulation, manifesting that antigen presentation in innate immune response was notably inhibited. Lipid metabolism-associated turbulence was noted in liver. We established a 3-biomarker signature depicting the metabolic-induced immune turbulence of HBV-ACLF. APOE induced cholesterol efflux may play an essential role in Kupfer cell polarization along HBV-ACLF deterioration, which can be reversed by rosuvastatin. Conclusions The results identified that the featured immune phenotypes in the liver microenvironment were potentially related to lipid metabolic turbulence in HBV-ACLF development, highlighting the presence of novel immune heterogeneity among different COSSH-ACLF grades, as well as between that between circulation and liver focal microenvironment.