DAPT 治疗后 NOTCH 信号抑制通过阻断 M1 和增强 M2 极化加剧肺泡包虫病肝纤维化,The FASEB Journal

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DAPT 治疗后 NOTCH 信号抑制通过阻断 M1 和增强 M2 极化加剧肺泡包虫病肝纤维化
The FASEB Journal ( IF 4.4 ) Pub Date : 2023-04-01 , DOI: 10.1096/fj.202202033r
Bin Li ₁ , Liang Wang _{1,

2} , Xinwei Qi ₂ , Yumei Liu ₃ , Jiajun Li ₁ , Jie Lv ₁ , Xuan Zhou ₁ , Xuanlin Cai ₂ , Jiaoyu Shan ₄ , Xiumin Ma _{1,

2}

Affiliation

肺泡包虫病 (AE) 是由多房棘球蚴( E. multilocularis )持续感染引起的致命性肝蠕虫病。尽管越来越多的人关注多房棘球蚴感染中的巨噬细胞，但很少研究巨噬细胞极化机制这一肝脏免疫的关键参与者。NOTCH 信号涉及细胞存活和巨噬细胞介导的炎症，但 NOTCH 信号在 AE 中的作用同样难以捉摸。在这项研究中，收集了 AE 患者的肝组织样本和多房肠球菌建立阻断 NOTCH 信号通路或不阻断 NOTCH 信号通路的感染小鼠模型，分析多房棘球蚴感染后肝脏的 NOTCH 信号通路、纤维化和炎症反应。通过流式细胞术分析肝巨噬细胞的极化和来源的变化。进行了体外 qRT-PCR 和蛋白质印迹分析以分析 NOTCH 信号传导中的关键受体和配体。我们的数据表明肝纤维化在 AE 后发展，DAPT 治疗引起的 NOTCH 信号传导的整体阻断加剧了肝纤维化的水平并改变了肝巨噬细胞的极化和起源。阻断E. multilocularis后巨噬细胞中的 NOTCH 信号感染下调 M1 并上调 M2 表达。NOTCH 信号通路中 NTCH3 和 DLL-3 的下调是显着的。因此，NOTCH3/DLL3 可能是 NOTCH 信号调节巨噬细胞极化影响 AE 引起的纤维化的关键通路。

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NOTCH signaling inhibition after DAPT treatment exacerbates alveolar echinococcosis hepatic fibrosis by blocking M1 and enhancing M2 polarization

Alveolar echinococcosis (AE) is a lethal helminthic liver disease caused by persistent infection with Echinococcus multilocularis (E. multilocularis). Although more and more attention has been paid to the macrophages in E. multilocularis infection, the mechanism of macrophage polarization, a critical player in liver immunity, is seldom studied. NOTCH signaling is involved in cell survival and macrophage-mediated inflammation, but the role of NOTCH signaling in AE has been equally elusive. In this study, liver tissue samples from AE patients were collected and an E. multilocularis infected mouse model with or without blocking NOTCH signaling was established to analyze the NOTCH signaling, fibrotic and inflammatory response of the liver after E. multilocularis infection. Changes in polarization and origin of hepatic macrophages were analyzed by flow cytometry. In vitro qRT-PCR and Western blot assays were performed to analyze key receptors and ligands in NOTCH signaling. Our data demonstrated that hepatic fibrosis develops after AE, and the overall blockade of NOTCH signaling caused by DAPT treatment exacerbates the levels of hepatic fibrosis and alters the polarization and origin of hepatic macrophages. Blocking NOTCH signaling in macrophages after E. multilocularis infection downregulates M1 and upregulates M2 expression. The downregulation of NTCH3 and DLL-3 in the NOTCH signaling pathway is significant. Therefore, NOTCH3/DLL3 may be the key pathway in NOTCH signaling regulating macrophage polarization affecting fibrosis caused by AE.

更新日期：2023-04-05

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