Fig. 2

The molecular mechanisms associated with different immune cells, including monocytes, macrophages, Th17 cells, NK cells, and NKT cells, participate in the modulation of HSC activation during HBV infection. HBV promotes lncRNA-HEIM expression in monocytes to induce TGF-β activation, following which HSCs are activated. HBV stimulation can upregulate KLRG1 expression in NK cells, and KLRG1 + NK cells are capable of inducing HSC apoptosis in a TRAIL-DR5-dependent manner. During HBV infection, NKT cells activate HSCs through IL-4 and IL-13. HBV induces Th17 cell recruitment to the liver via CCL17 and CCL22. HBV activates Th17 cells via IL-23 secreted by macrophages. HBcAg stimulates Th17 cell activation via IL-6R. Activated Th17 cells secrete IL-17 and IL-22 to activate HSCs via activating PI3K. In addition, IL-17 activates HSCs by interacting with IL-17R to facilitate activation of the P38 and ERK1/2 pathways. IL-17 activates JNK and positively regulates the TGF-βR-Smad2/3 pathway. HBsAg and HBeAg promote SIRT1 expression and then induce Notch 1 deacetylation to inhibit NF-κB, but they activate AKT to induce macrophage differentiation toward M2. M2 macrophages activate HSCs by producing and secreting TGF-β. HBeAg induces macrophage activation through TLR2 and activates the NF-κB pathway to upregulate the expression and increase the secretion of CCL2, TNF-α, CCL5, and CXCL10. These cytokines and chemokines activate the PI3K-mTOR and P38 pathways in HSCs to facilitate HSC activation