Department of Paediatric Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110004, PR China.
Department of Paediatrics, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110004, PR China.
EBioMedicine. 2024 Oct;108:105344. doi: 10.1016/j.ebiom.2024.105344. Epub 2024 Sep 16.
Biliary atresia (BA) is a devastating neonatal cholangiopathy with an unclear pathogenesis, and prompt diagnosis of BA is currently challenging.
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.
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-33 expression, and boosted hepatic Th2 inflammation in BA mouse model. PIGR expression promotes the proliferation and epithelial-mesenchymal transition, and reduced the apoptosis of BECs.
PIGR participated in BA pathogenesis by promoting hepatic Th2 inflammation via increasing cholangiocytes derived IL-33; PIGR has the value as a diagnostic and therapeutic biomarker of BA.
This study was financially supported by the National Natural Science Foundation of China (82170529), the National Key R&D Program (2021YFC2701003), and the National Natural Science Foundation of China (82272022).
胆道闭锁（BA）是一种具有不明发病机制的毁灭性新生儿胆管病，目前对 BA 的诊断仍然具有挑战性。
使用 250 名患者的血清样本进行蛋白质组学和免疫分析，以寻找潜在的 BA 生物标志物。使用人活检样本、三种不同的实验性小鼠模型和培养的人胆管上皮细胞（BEC）研究了多聚免疫球蛋白受体（PIGR）的表达特征。化学修饰的小干扰 RNA 和腺病毒表达载体被用于轮状病毒诱导的 BA 小鼠模型中 PIGR 的体内沉默和过表达。采用基于 Luminex 的多重细胞因子测定和 RNA 测序来探讨 PIGR 参与 BA 发病机制的分子机制。
BA 患者的血清 PIGR、脊髓灰质炎病毒受体（PVR）和醛缩酶 B（ALDOB）水平升高，并能准确地区分 BA 与婴儿肝炎综合征（IHS）。联合 PIGR 和 PVR 分析以 0.968 的受试者工作特征曲线下面积和 0.935 的准确率区分 BA 与 IHS。BA 患者的胆管上皮中 PIGR 表达上调；TNF-α 和 IFN-γ 等 Th1 细胞因子通过激活 NF-κB 通路诱导 BEC 中 PIGR 的表达。在 BA 小鼠模型中，沉默 PIGR 可减轻症状、降低 IL-33 表达并抑制肝 Th2 炎症；而在 BA 小鼠模型中过表达 PIGR 则增加肝纤维化和 IL-33 表达并促进肝 Th2 炎症。PIGR 表达促进 BEC 的增殖和上皮-间充质转化，并减少 BEC 的凋亡。
PIGR 通过增加胆管细胞来源的 IL-33 促进肝 Th2 炎症而参与 BA 发病机制；PIGR 具有作为 BA 诊断和治疗生物标志物的价值。
本研究得到国家自然科学基金（82170529）、国家重点研发计划（2021YFC2701003）和国家自然科学基金（82272022）的资助。
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