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 <UnorderedList Mark="Bullet"> <ItemContent> 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. </ItemContent> <ItemContent> In vivo inhibition of TLR4 or a reduction in LPS levels alleviates symptoms in newborn mice injected with RRV. </ItemContent> <ItemContent> 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. </ItemContent> </UnorderedList>

Biliary atresia: Rotavirus amplification of lipopolysaccharide/toll-like receptor 4 by mediating MMP7 upregulation through NF-κB

期刊论文
发表日期：

2025年5月25日

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Shuiqing Chi,
Liying Rong,
Mengxin Zhang,
Yibo Li,
Yun Zhou,
Xiangyang Li,
Xi Zhang,
Zhibin Luo,
Shuai Li,
Guoqing Cao,
Shao-tao Tang

摘要

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.