Hepatic macrophage niche: a bridge between HBV-mediated metabolic changes with intrahepatic inflammation

Abstract

Hepatitis B Virus (HBV) is a stealthy and insidious pathogen capable of inducing chronic necro-inflammatory liver disease and hepatocellular carcinoma (HCC), resulting in over one million deaths worldwide per year. The traditional understanding of Chronic Hepatitis B (CHB) progression has focused on the complex interplay among ongoing virus replication, aberrant immune responses, and liver pathogenesis. However, the dynamic progression and crucial factors involved in the transition from HBV infection to immune activation and intrahepatic inflammation remain elusive. Recent insights have illuminated HBV's exploitation of the sodium taurocholate co-transporting polypeptide (NTCP) and manipulation of the cholesterol transport system shared between macrophages and hepatocytes for viral entry. These discoveries deepen our understanding of HBV as a virus that hijacks hepatocyte metabolism. Moreover, hepatic niche macrophages exhibit significant phenotypic and functional diversity, zonal characteristics, and play essential roles, either in maintaining liver homeostasis or contributing to the pathogenesis of chronic liver diseases. Therefore, we underscore recent revelations concerning the importance of hepatic niche macrophages in the context of viral hepatitis. This review particularly emphasizes the significant role of HBV-induced metabolic changes in hepatic macrophages as a key factor in the transition from viral infection to immune activation, ultimately culminating in liver inflammation. These metabolic alterations in hepatic macrophages offer promising targets for therapeutic interventions and serve as valuable early warning indicators, shedding light on the disease progression.

Keywords: HBV; hepatic macrophage niches; lipid metabolism (fatty acids); liver inflammation; metabolism.

Figure 1

Model of HBV entry into hepatocytes via two routes. First Route: ① Enveloped hepatitis B virus (HBV) particles circulate within the sinusoidal blood, traversing the fenestrae of sinusoidal endothelial cells to access the space of Disse. Eventually, they reach the integral membrane protein receptor NTCP, which concurrently impedes the transport of bile acids. ② Repressed bile acid transport inhibits the farnesoid X receptor/small heterodimer partner (FXR/SHP) signaling pathway, leading to the compulsory upregulation of the transcription factor Cytochrome P450 Family 7 Subfamily A Member 1 (CYP7A1) ③. ④ Increased CYP7A1 accelerates the reversed transport of cholesterol and promotes the synthesis of bile acids. ⑤ The low density lipoprotein receptor (LDLR) pathway is activated, further promoting the process of bile acid synthesis. Second Route: ① HBV became entrapped within serum triglyceride-rich lipoproteins (TRL), traverse the endothelial cell layer to access the space of Disse. Once there, they are ensnared through electrostatic interactions with HSPG (heparan sulfate proteoglycan) before ultimately binding with NTCP (sodium taurocholate co-transporting polypeptide). ② ③ When associated with lipoproteins, HBV is preferentially internalized by liver macrophages into recycling endosomes. ④ Subsequently, HBV particles enter hepatocytes. Cholesterol esters of endocytosed lipoproteins undergo hydrolysis by the endosomal acid lipase, liberating free cholesterol. This free cholesterol is then conveyed to the cell membrane, released from the macrophage, and can bind to extracellular lipid receptors, facilitating additional uptake into hepatocytes. The figure was created by BioRender (BioRender.com).

Figure 2

Computational docking analyses were performed to examine the interactions between HBcAg, HBsAg, and HBeAg proteins with APOE molecules, shedding light on potential molecular associations. Display of docking results between representative HBcAg (protein ID, Q9E6S6) (A), HBsAg (protein ID, Q9E6S4) (B), HBeAg (protein ID, P0C6H2) (C) proteins, and APOE (protein ID, P02649) molecules. The protein IDs were obtained from UniProt (https://www.uniprot.org/). The yellow protein represents APOE, and the Cyan protein represents HBV. Local graphs depict the Top 5 polar bonds with the closest distances in the docking results. Red denotes oxygen (O) atoms, and blue denotes nitrogen (N) atoms. Numbers indicate the distances between atoms forming polar bonds (unit: angstroms, Å). (D) The table displays the top 15 results of the 'balance' calculation weight scores, obtained through the Cluspro2 online analysis platform using the interface root mean square deviation (IRMSD) method. A1, A2, A3, B1, B2, C represent different HBV subtypes, each uniquely identified by specific protein IDs obtained from UniProt (https://www.uniprot.org/). The protein IDs for HBeAg are as follows: Q91C37 (A1 subgenotype), P0C692 (A2 subgenotype), Q4R1S0 (A3 subgenotype), P0C699 (B1 subgenotype), P0C6G7 (B2 subgenotype), P0C6H2 (C subgenotype); The protein IDs for HBsAg are as follows: P31873 (A1 subgenotype), O91534 (A2 subgenotype), Q4R1S6 (A3 subgenotype), Q9QBF0 (B1 subgenotype), Q9QAB7 (B2 subgenotype), Q9E6S4 (C subgenotype); The protein IDs for HBcAg are as follows: I7JHV6 (A1 subgenotype), P0C696 (A2 subgenotype), P0C697 (A3 subgenotype), P0C677 (B1 subgenotype), Q9QAB9 (B2 subgenotype), Q9E6S6 (C subgenotype); The protein IDs for AOPE is P02649. A higher value, represented by a darker red shade in (D), corresponds to a stronger polar bond energy, suggesting a more favorable and robust binding between the two proteins.

Figure 3

Hypothesis on the process of how HBV induces liver injury. ① Accumulation of metabolites, including bile acids and cholesterol, in the liver. ② Metabolism alteration promotes the expression of pro-inflammatory signaling like Toll-like receptors (TLRs) in hepatocytes, leading to the transition of highly heterogeneous hepatic macrophages into a pro-inflammatory phenotype characterized by increased expression of pro-inflammatory cytokines and activation of specific signaling pathways. ③ More inflammatory cells are recruited into the liver through the release of chemokines like CXCL9/10. ④ Within the highly heterogeneous hepatic macrophages, the presence of at least five potential clusters can be identified in both physiological and pathological states of the liver (e.g., Acute-on-Chronic Liver Failure, ACLF; Chronic hepatitis B, CHB…). Each cluster is associated with specific marker genes and potential functions. ⑤ The phenotypic and functional transitions may exhibit variation across different stages of CHB and diverse liver regions. The figure was created by BioRender (BioRender.com).

Figure 4

The potential immunopathology of how HBV shapes hepatic macrophage niches, ultimately leading to liver inflammation. ① Persistent HBV stimulation induces abnormal lipid metabolism, characterized by the accumulation of metabolites such as bile acids and cholesterol in the liver microenvironment. ② The aberrant lipid metabolism triggers an innate immune response by releasing PAMPs, such as the up-regulation of TLRs’ expression in hepatocytes, and DAMPs released by damaged hepatocyte mitochondria. ③ The accumulation of lipids recruits a specific cluster of macrophages, possibly Lipid-Associated Macrophages (LAMs), identified by the expression of Trem2, triggering a transition into a pro-inflammatory phenotype. ④ The activated LAMs exhibit a distinctive transcriptomic profile with elevated expression of IL-1β, IL-6, IL-12, TNF-α, CCL18, CXCL9/10, MMP7, MMP12, M1F, S100A8/A9, leading to the recruitment of more inflammatory cells. ⑤ Deepening liver inflammation occurs as a result of increased infiltration of inflammatory cells into the liver. The figure was created by BioRender (BioRender.com).