Cell-type-specific expression analysis of liver transcriptomics with clinical parameters to decipher the cause of intrahepatic inflammation in chronic hepatitis B

Wang, Jun1,2,3,4,5,6; Li, Qian1,2,3; Qiu, Yuanwang4; Kitanovski, Simo5,6; Wang, Chen1,2; Zhang, Chenxia4; Li, Fahong7; Li, Xiaoguang4; Zhang, Zhenfeng8; Huang, Lihua4; Zhang, Jiming7; Hoffmann, Daniel5,6; Lu, Mengji1,2,3,4; Lu, Hongzhou1,2

2024-07-01

10.1002/imt2.221

IMETA   影响因子和分区

2770-5986

2770-596X

["Functional cure for chronic hepatitis B (CHB) remains challenging due to the lack of direct intervention methods for hepatic inflammation. Multi-omics research offers a promising approach to understand hepatic inflammation mechanisms in CHB. A Bayesian linear model linked gene expression with clinical parameters, and population-specific expression analysis (PSEA) refined bulk gene expression into specific cell types across different clinical phases. These models were integrated into our analysis of key factors like inflammatory cells, immune activation, T cell exhaustion, chemokines, receptors, and interferon-stimulated genes (ISGs). Validation through multi-immune staining in liver specimens from CHB patients bolstered our findings. In CHB patients, increased gene expression related to immune cell activation and migration was noted. Marker genes of macrophages, T cells, immune-negative regulators, chemokines, and ISGs showed a positive correlation with serum alanine aminotransferase (ALT) levels but not hepatitis B virus DNA levels. The PSEA model confirmed T cells as the source of exhausted regulators, while macrophages primarily contributed to chemokine expression. Upregulated ISGs (ISG20, IFI16, TAP2, GBP1, PSMB9) in the hepatitis phase were associated with T cell and macrophage infiltration and positively correlated with ALT levels. Conversely, another set of ISGs (IFI44, ISG15, IFI44L, IFI6, MX1) mainly expressed by hepatocytes and B cells showed no correlation with ALT levels. Our study presents a multi-omics analysis integrating bulk transcriptomic, single-cell sequencing data, and clinical data from CHB patients to decipher the cause of intrahepatic inflammation in CHB. The findings confirm that macrophages secrete chemokines like CCL20, recruiting exhausted T cells into liver tissue; concurrently, hepatocyte innate immunity is suppressed, hindering the antiviral effects of ISGs.","This study integrates liver bulk transcriptomic data, single-cell sequencing data, and clinical data to analyze the factors that induce hepatic inflammation in chronic hepatitis B from a multi-omics perspective by Bayesian regression. Macrophages secrete chemokines like CCL20 and CXCL8 to recruit immune-exhausted T lymphocytes (CTLA4, TIGIT) into liver tissue. Innate immunity within hepatocytes is suppressed, impeding interferon-stimulated genes from initiating antiviral effects. Activation of innate immune pathways in infiltrating T cells and macrophages further exacerbates inflammation formation. image","This study integrates liver bulk transcriptomic data, single-cell sequencing data, and clinical data to analyze the factors inducing hepatic inflammation in chronic hepatitis B from a multi-omics perspective by Bayesian regression. Macrophages secrete chemokines like CCL20 and CXCL8 to recruit immune-exhausted T lymphocytes (CTLA4, TIGIT) into liver tissue. Innate immunity within hepatocytes is suppressed, impeding interferon-stimulated genes from initiating antiviral effects. Activation of innate immune pathways in infiltrating T cells and macrophages further exacerbates inflammation formation."]

chronic hepatitis B immune infiltration innate immunity population-specific expression analysis

ESCI

英语

第一 ; 通讯

National Science Foundation of China[82072281] ; China Postdoctoral Science Foundation["2022M721473","2022M711486"] ; Basic Research Foundation of Guangdong Province["2022A1515111163","2020A15151108031"] ; Sino-Germany Mobility Program[M-0569] ; Top Talent Support Program for Young and Middleaged People of Wuxi Health Committee[BJ2023093]

Microbiology

Microbiology

WOS:001261671900001

WILEY

Web of Science

1.Southern Univ Sci & Technol, Peoples Hosp Shenzhen 3, Natl Clin Res Ctr Infect Dis, Shenzhen, Peoples R China
2.Southern Univ Sci & Technol, Affiliated Hosp 2, Shenzhen, Peoples R China
3.Univ Duisburg Essen, Univ Hosp Essen, Inst Virol, Essen, Germany
4.Jiangnan Univ, Peoples Hosp Wuxi 5, Clin Med Res Ctr, Wuxi, Peoples R China
5.Univ Duisburg Essen, Fac Biol, Bioinformat & Computat Biophys, Essen, Germany
6.Univ Duisburg Essen, Ctr Med Biotechnol ZMB, Essen, Germany
7.Fudan Univ, Huashan Hosp, Shanghai Inst Infect Dis & Biosecur, Shanghai Key Lab Infect Dis & Biosafety Emergency, Shanghai, Peoples R China
8.Southern Univ Sci & Technol, Sch Publ Hlth & Emergency Management, Shenzhen, Peoples R China

Wang, Jun,Li, Qian,Qiu, Yuanwang,et al. Cell-type-specific expression analysis of liver transcriptomics with clinical parameters to decipher the cause of intrahepatic inflammation in chronic hepatitis B[J]. IMETA,2024.

Wang, Jun.,Li, Qian.,Qiu, Yuanwang.,Kitanovski, Simo.,Wang, Chen.,...&Lu, Hongzhou.(2024).Cell-type-specific expression analysis of liver transcriptomics with clinical parameters to decipher the cause of intrahepatic inflammation in chronic hepatitis B.IMETA.

Wang, Jun,et al."Cell-type-specific expression analysis of liver transcriptomics with clinical parameters to decipher the cause of intrahepatic inflammation in chronic hepatitis B".IMETA (2024).