Stimulation of the STING pathway leads to inhibition of HBV replication: insights into the role of hepatic macrophages.

Abstract

Activation of the host immune system is a promising strategy for treating hepatitis B (HBV). The stimulator of interferon genes (STING) signaling pathway acts as an innate immune sensor for viral DNA. We aimed to determine whether STING activation can inhibit HBV replication in the liver. We evaluated STING expression in peripheral blood mononuclear cells (PBMCs) and liver biopsy specimens from patients with chronic hepatitis B (CHB). We examined the effect of the STING agonist DMXAA on HBV replication and the immune response in a mouse model with persistent HBV replication (rAAV8-HBV1.3). Additionally, we depleted macrophages in vivo to assess their role in DMXAA's antiviral effects. STING expression in CHB patients was higher in the immune-active phase than in the inactive phase or uninfected healthy controls, suggesting an association between elevated STING expression and immune activation. In a mouse model with persistent HBV replication, DMXAA reduced serum HBV DNA in a dose-dependent manner, whereas repeated administration reduced serum HBV DNA, HBsAg, and HBeAg levels and enhanced hepatic immune responses. Transcriptome sequencing of liver tissues revealed 856 differentially expressed genes (DEGs) involved in immune-related signaling pathways. In hepatic macrophage-depleted mice, the reductions in HBV virological markers following DMXAA treatment were less pronounced. STING pathway activation enhances the immune response against HBV by upregulating the expression of immune-related genes. Hepatic macrophages play an important role in STING-mediated inhibition of HBV replication.