Polymeric immunoglobulin receptor promotes Th2 immune response in the liver by increasing cholangiocytes derived IL-33: a diagnostic and therapeutic biomarker of biliary atresia

作者：Yuan Li, Tianyu Li, Qi Qiao, Min‐Ting Zhang, Ming‐Xin Tong, Lingfen Xu, Zhibo Zhang · 发表于：EBioMedicine · 年份：2024 · DOI：10.1016/j.ebiom.2024.105344 · 被引用次数：9 · 研究领域：Pediatric Hepatobiliary Diseases and Treatments、Liver Diseases and Immunity、Infant Nutrition and Health

BACKGROUND: Biliary atresia (BA) is a devastating neonatal cholangiopathy with an unclear pathogenesis, and prompt diagnosis of BA is currently challenging. METHODS: Proteomic and immunoassay analyses were performed with serum samples from 250 patients to find potential BA biomarkers. The expression features of polymeric immunoglobulin receptor (PIGR) were investigated using human biopsy samples, three different experimental mouse models, and cultured human biliary epithelial cells (BECs). Chemically modified small interfering RNA and adenovirus expression vector were applied for in vivo silencing and overexpressing PIGR in a rotavirus-induced BA mouse model. Luminex-based multiplex cytokine assays and RNA sequencing were used to explore the molecular mechanism of PIGR involvement in the BA pathogenesis. FINDINGS: Serum levels of PIGR, poliovirus receptor (PVR), and aldolase B (ALDOB) were increased in BA patients and accurately distinguished BA from infantile hepatitis syndrome (IHS). Combined PIGR and PVR analysis distinguished BA from IHS with an area under the receiver operating characteristic curve of 0.968 and an accuracy of 0.935. PIGR expression was upregulated in the biliary epithelium of BA patients; Th1 cytokines TNF-α and IFN-γ induced PIGR expression in BECs via activating NF-κB pathway. Silencing PIGR alleviated symptoms, reduced IL-33 expression, and restrained hepatic Th2 inflammation in BA mouse model; while overexpressing PIGR increased liver fibrosis and IL...