Down-regulation of STAT3 enhanced chemokine expression and neutrophil recruitment in biliary atresia.
Down-regulation of STAT3 enhanced chemokine expression and neutrophil recruitment in biliary atresia.
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STAT3 下调增强胆道闭锁趋化因子表达和中性粒细胞募集
DOI：
10.1042/cs20201366
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发表时间：
2021-04-16
期刊：
影响因子：
--
通讯作者：
Chen Y
中科院分区：
文献类型：
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作者：
Fu M;Tan L;Lin Z;Lui VCH;Tam PKH;Lamb JR;Zhang Y;Xia H;Zhang R;Chen Y
摘要胆道闭锁（BA）是一种免疫相关疾病，信号转导和转录激活因子3（STAT 3）是炎症反应中的关键信号分子。本研究旨在阐明STAT 3在BA中的功能。在患者和小鼠BA模型中检查了STAT 3表达，其中用特异性抑制剂或激活剂进一步改变了STAT 3水平。测定中性粒细胞蓄积和中性粒细胞化学引诱物（C-X-C基序）配体1（CXCL 1）和IL-8的水平。在人胆管上皮细胞（BEC）培养物中检测STAT 3抑制对IL-8表达的影响。用10×单细胞RNA-seq方法分析小鼠模型中肝脏STAT 3+中性粒细胞的功能变化。结果显示，与对照组相比，BA肝组织中STAT 3和p-STAT 3的表达降低。STAT 3抑制剂的施用增加了BA小鼠的黄疸和死亡率，并降低了体重。相反，STAT 3激活剂改善BA症状。广泛的中性粒细胞积累与CXCL 1上调，这两者都被抑制的抗CXCL 1抗体，在STAT 3的治疗组中观察到。重组IL-8给药增加了BA小鼠的疾病严重程度，而STAT 3激活剂具有相反的作用。抑制STAT 3增加了人BEC的凋亡以及上调的IL-8表达。RNA-seq分析显示BA中表达STAT 3的中性粒细胞的数量减少，这伴随着干扰素相关的抗病毒活性的显著增强。总之，STAT 3的减少，增强IL-8和CXCL 1的表达，并促进干扰素反应性中性粒细胞的积累，导致BEC损伤BA。
Abstract Biliary atresia (BA) is an immune-related disorder and signal transducer and activator of transcription 3 (STAT3) is a key signalling molecule in inflammation. The present study was designed to clarify the function of STAT3 in BA. STAT3 expression was examined in patients and a mouse BA model in which STAT3 levels were further altered with a specific inhibitor or activator. Neutrophil accumulation and the levels of the neutrophil chemoattractants (C–X–C motif) ligand 1 (CXCL1) and IL-8 were determined. The effects of STAT3 inhibition on IL-8 expression were examined in human biliary epithelial cell (BEC) cultures. Functional changes in liver STAT3+ neutrophils in the mouse model were analysed with 10× single cell RNA-seq methods. Results showed STAT3 and p-STAT3 expression was reduced in BA liver tissue compared with control samples. Administration of a STAT3 inhibitor increased jaundice and mortality and reduced body weight in BA mice. In contrast, the STAT3 activator ameliorated BA symptoms. Extensive neutrophil accumulation together with CXCL1 up-regulation, both of which were suppressed by an anti-CXCL1 antibody, were observed in the STAT3 inhibitor-treated group. Recombinant IL-8 administration increased disease severity in BA mice, and the STAT3 activator had the reverse effect. Inhibiting STAT3 increased apoptosis of human BECs together with up-regulated IL-8 expression. RNA-seq analysis revealed reduced the numbers of STAT3 expressing neutrophil in BA which was accompanied by marked enhanced interferon-related antiviral activities. In conclusion, STAT3 reduction, enhanced IL-8 and CXCL1 expression and promoted the accumulation of interferon-responsive neutrophils resulting in BEC damage in BA.