This study reveals the critical role of the IL-8-CXCR2 signaling axis in NETosis in children with biliary atresia and, for the first time, confirms that NETs can directly activate hepatic stellate cells, providing new mechanistic insights into fibrosis progression.
Literature Overview
The article, titled 'IL-8-CXCR2 Pathway Mediates Neutrophil Extracellular Trap Formation in Biliary Atresia,' published in the journal Hepatology, reviews and summarizes the mechanisms by which neutrophils are persistently activated in biliary atresia patients, leading to NET formation. It also presents evidence showing that NETs promote liver fibrosis through the release of tissue factor and IL-17A. The study further demonstrates that IL-8 induces NETosis via the CXCR2 receptor, and blocking this pathway significantly suppresses NET formation, offering new perspectives for targeted therapies.Background Knowledge
Biliary atresia is a rare but severe inflammatory disease of the bile ducts in infants, ultimately leading to bile stasis and cirrhosis. Despite the availability of Kasai surgery, most patients still require liver transplantation. In recent years, neutrophil extracellular traps (NETs) have been extensively studied for their pathogenic roles in various inflammatory and autoimmune diseases, but their exact mechanisms in biliary atresia remain unclear. IL-8 (CXCL8), as a neutrophil chemokine and NET activator, has been shown to have expression levels that correlate with the severity of liver injury and fibrosis in biliary atresia. Using multi-omics and functional validation approaches, this study systematically reveals the pro-fibrotic role of NETs in biliary atresia and their association with the IL-8-CXCR2 pathway, offering a theoretical basis for developing targeted therapeutic strategies.
Research Methods and Experiments
The research team obtained plasma and tissue samples from biliary atresia patients and control groups at diagnosis and liver transplantation stages via the Childhood Liver Disease Research Network (ChiLDReN). Plasma levels of neutrophil elastase, NET markers (MPO-DNA complexes), and IL-8 were measured by ELISA. Neutrophil NETosis and CXCR2 receptor expression were analyzed using flow cytometry. NET localization and density in liver tissues were evaluated by immunohistochemistry and multiplex fluorescence staining. Isolated NETs were co-cultured with LX2 hepatic stellate cells to assess changes in ACTA2 and COL1A1 expression, collagen secretion, and cell surface marker expression.Key Conclusions and Perspectives
Research Significance and Prospects
This study, for the first time, reveals the pro-fibrotic role of NETs in biliary atresia and establishes the central role of the IL-8-CXCR2 axis in NET formation. Future studies may further evaluate the therapeutic efficacy of NET inhibitors (e.g., DNAse1, Reparixin) in animal models, and explore whether targeting IL-8 or CXCR2 can improve fibrosis associated with biliary atresia. Additionally, the dynamic expression of NETs across disease stages and their cross-regulation with immune cells (e.g., T cells, B cells) warrants further investigation.
Conclusion
Through systematic analysis of NET formation and its regulatory mechanisms in plasma and liver tissues of biliary atresia patients, this study clarifies the central role of the IL-8-CXCR2 pathway in NETosis and demonstrates that NETs can directly activate hepatic stellate cells to promote fibrosis. These findings not only expand the understanding of the immunopathological mechanisms of biliary atresia but also provide preclinical evidence for therapeutic strategies targeting NET-related factors. Future research should integrate animal models and single-cell sequencing technologies to further dissect the functional roles of NETs in bile stasis and liver fibrosis progression, and explore the potential application of small molecule inhibitors targeting this pathway in biliary atresia.
