GHSR and TLR4 collectively promote hepatic inflammation and aberrant repair in alveolar echinococcosis.

BACKGROUND AND

OBJECTIVE

Alveolar echinococcosis (AE) is a fatal zoonotic parasitic disease that causes progressive hepatic injury through chronic inflammation, aberrant proliferative repair, and liver fibrosis. GHSR and TLR4 individually regulate hepatic inflammation and proliferation; however, their synergistic roles in Echinococcus multilocularis (E. multilocularis)-induced AE remain unclear.

METHODS

Wild-type (WT), GHSR-knockout (GHSR-/-), and TLR4-knockout (TLR4-/-) murine AE models were established, and comprehensive evaluations of hepatic pathology, cell proliferation, macrophage polarization, inflammatory factors, and hepatic proteomic profiles were performed at 12 weeks post-infection.

RESULTS

Knockout of either GHSR or TLR4 alleviated AE-induced hepatic lesions, fibrosis, and liver dysfunction. Mechanistically, their deletion suppressed PI3K/Akt-mediated proliferation and TLR4/MyD88/NF-κB-mediated inflammation, reduced M1/M2 macrophage infiltration, decreased pro-inflammatory cytokines (IL-6, TNF-α, and TGF-β1), and elevated anti-inflammatory IL-10. A positive expression correlation between GHSR and TLR4 was confirmed in AE, Proteomics further verified their coordinated modulation of hepatic inflammation and aberrant repair.

CONCLUSIONS

Collectively, upregulated GHSR and TLR4 jointly promote Echinococcus multilocularis-associated hepatic damage via sustaining persistent inflammation and dysregulated proliferative tissue repair. This study demonstrates coordinated pro-pathological involvement of GHSR and TLR4 in AE progression and provides in vivo and proteomic evidence supporting the exploration of targeted interventions against parasitic liver disorders.