CXCL1型
趋化因子
胆管
生物
炎症
免疫学
间质细胞
细胞生物学
胆管上皮细胞
CXCL2型
癌症研究
趋化因子受体
医学
内科学
内分泌学
作者
Nureen H. Mohamad Zaki,Junya Shiota,Ashley Calder,Theresa M. Keeley,Benjamin L. Allen,Kazuwa Nakao,Linda C. Samuelson,Nataliya Razumilava
出处
期刊:Hepatology
[Wiley]
日期:2022-04-30
卷期号:76 (4): 936-950
被引量:3
摘要
In extrahepatic bile duct (EHBD) cholangiopathies, including primary sclerosing cholangitis, a reactive cholangiocyte phenotype is associated with inflammation and epithelial hyperproliferation. The signaling pathways involved in EHBD injury response are poorly understood. In this study, we investigated the role of Hedgehog (HH) signaling and its downstream effectors in controlling biliary proliferation and inflammation after EHBD injury.Using mouse bile duct ligation as an acute EHBD injury model, we used inhibitory paradigms to uncover mechanisms promoting the proliferative response. HH signaling was inhibited genetically in Gli1-/- mice or by treating wild-type mice with LDE225. The role of neutrophils was tested using chemical (SB225002) and biological (lymphocyte antigen 6 complex locus G6D [Ly6G] antibodies) inhibitors of neutrophil recruitment. The cellular response was defined through morphometric quantification of proliferating cells and CD45+ and Ly6G+ immune cell populations. Key signaling component expression was measured and localized to specific EHBD cellular compartments by in situ hybridization, reporter strain analysis, and immunohistochemistry. Epithelial cell proliferation peaked 24 h after EHBD injury, preceded stromal cell proliferation, and was associated with neutrophil influx. Indian HH ligand expression in the biliary epithelium rapidly increased after injury. HH-responding cells and neutrophil chemoattractant C-X-C motif chemokine ligand 1 (CXCL1) expression mapped to EHBD stromal cells. Inhibition of HH signaling blocked CXCL1 induction, diminishing neutrophil recruitment and the biliary proliferative response to injury. Directly targeting neutrophils by inhibition of the CXCL1/C-X-C motif chemokine receptor 2/Ly6G signaling axis also decreased biliary proliferation.HH-regulated CXCL1 orchestrates the early inflammatory response and biliary proliferation after EHBD injury through complex cellular crosstalk.
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