Role of HMGB1/TLR4/NF-κB signaling pathway-mediated pyroptosis in the mechanism of novel goose astrovirus-induced kidney injury in goslings

As a novel type of highly lethal astrovirus, the Goose Astrovirus (GoAstV) can cause severe gout-like damage to the kidneys of young geese. However, the pathogenesis of GoAstV infection leading to gosling renal gout has not been clearly described, and the mediating pathways of inflammation and pyroptosis during this pathogenic process remain unclear. This study shown that GoAstV infection caused swelling of renal tubular epithelial cells and that inflammatory cells infiltrated the renal interstitium. The mitochondrial ridge arrangement of the cells was disordered, and clear viral particles were observed in the cytoplasm. The transcriptomic results of renal tissues 6 days after GoAstV infection showed that there were 2594 differentially expressed genes between the comparison groups. After comparison with the Go and KEGG databases, it was found that these genes were mainly enriched in the NF-κB, Toll-like receptor, NOD-like receptor and cytokine receptor interaction pathways. Meanwhile, GoAstV infection led to cell membrane damage and an increase in the release of inflammatory cytokines and lactate dehydrogenase. GoAstV significantly increased the expression levels of related genes and proteins in the HMGB1/TLR4/NF-κB and NLRP3-mediated signaling pathways. Given this, after adding glycyrrhizin and MCC950 in vitro, the HMGB1/TLR4/NF-κB pathway was inhibited, resulting in a decrease in NLRP3 expression, a reduction in the release of inflammatory cytokines, protection of cell membrane integrity. In summary, GoAstV triggers inflammation and pyroptosis through activating the HMGB1/TLR4/NF-κB signaling axis. These two processes are mutually causal and form a cascading amplification effect, jointly exacerbating the process of kidney gout damage.