INTRODUCTION: Hepatitis B virus (HBV) can cause kidney damage and lead to hepatitis B virus-associated glomerulonephritis (HBV-GN). Herein, the objectives were to establish a mouse model of HBV-GN to study the associated TLR3/TRIF pathway signaling, dendritic cells, the role of natural immunity in HBV-GN, and identify potential novel targets for treatment of HBV-GN. MRTHODS: BALB/c mice injected with serum from hepatitis B-infected patients were used to establish the HBV-GN model. Kidney damage was monitored by urinary protein analysis. Kidney sections were examined for HbsAg and tissue pathology. Affected mice also received interventions with the anti-HBV agent entecavir and entecavir plus the immunosuppressant mycophenolate mofetil. The expression levels of TLR3, TRIF, IRF3, and IFN-β in the kidney were analyzed by western blotting and RT-PCR. Flow cytometry was used to monitor kidney dendritic cell populations. RESULTS: Kidney damage was induced in mice by injection of HBV-infected serum. This was associated with infiltration of kidney tissue by large numbers of inflammatory cells and increased expression of TLR3, TRIF, IRF3, and IFN-β. Treatment with entecavir or entecavir+ mycophenolate mofetil resulted in lower expression levels, although this was still elevated compared to healthy control mice (no difference in expression levels between mice receiving entecavir vs. entecavir+ mycophenolate mofetil was observed). The number of dendritic cells were directly proportional to TLR3, TRIF, IRF3, and IFN-β expression levels across all experimental and control groups. CONCLUSIONS: An HBV-GN mouse model was successfully established by injection of serum HBV into BALB/c mice. Our observations are consistent with a mechanism whereby viral dsRNA may bind to TLR3 on dendritic cells to activate the TLR3/TRIF signaling pathway and stimulate dendritic cell maturation, promoting tissue inflammation and immune disequilibrium that causes kidney damage. These results suggest new strategies for HBV-GN treatment that target TLR3. (Am J Transl Med 2020. 4:140-150).