Pediatr Res. 2025 May 25. doi: 10.1038/s41390-025-04128-4. Online ahead of print.
ABSTRACT
BACKGROUND: Matrix metalloproteinase-7 (MMP7), which is expressed primarily by biliary epithelial cells (BECs), has been shown to promote biliary atresia (BA). However, the mechanism by which elevated MMP7 expression is induced in BA remains unclear.
METHODS: Mouse extrahepatic BECs were used to investigate MMP7 overexpression induced by rhesus rotavirus (RRV) and lipopolysaccharide (LPS). The cellular localization of TLR4 and related proteins in the liver specimens from model mice was analyzed by immunohistochemistry. In vivo experiments were performed in BA models with TLR4 inhibition or antibiotic treatment and their corresponding control groups.
RESULTS: RRV infection alone is insufficient to induce MMP7 expression in mouse extrahepatic BECs, whereas sequential RRV infection and low-dose LPS treatment could cause robust MMP7 overexpression. RRV disrupted BEC endotoxin tolerance via HMGB1-mediated TLR4 upregulation, which subsequently promoted NF-κB and MMP7 overexpression. BECs from experimental BA model mice presented significantly increased TLR4 expression and NF-κB activation. In vivo, treatment with TLR4 antibodies, inhibitors, or antibiotics reduced MMP7 production, alleviated disease severity, and improved survival rates in BA models.
CONCLUSION: RRV infection disrupts BEC tolerance to low-dose LPS, triggering TLR4/NF-κB-mediated MMP7 overexpression and hepatobiliary inflammation, advancing our understanding of the role of LPS/TLR4 signaling in BA pathogenesis.
IMPACT STATEMENT: Rhesus rotavirus infection induces the upregulation of TLR4 expression in BECs, disrupting their tolerance to physiological levels of LPS and resulting in robust activation of the NF-κB pathway and subsequent abundant expression of MMP7. In vivo inhibition of TLR4 or a reduction in LPS levels alleviates symptoms in newborn mice injected with RRV. This study underscores the crucial role of LPS/TLR4 pathway activation in the pathogenesis of biliary atresia, which may be a key potential therapeutic target.
PMID:40415071 | DOI:10.1038/s41390-025-04128-4
