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

• Published in: The FASEB journal 2023-05, Vol.37 (5), p.e22901-n/a
• Main Authors: Li, Bin, Wang, Liang, Qi, Xinwei, Liu, Yumei, Li, Jiajun, Lv, Jie, Zhou, Xuan, Cai, Xuanlin, Shan, Jiaoyu, Ma, Xiumin
• Format: Article
• Language: English
• Subjects: alveolar echinococcosis; Animals; E. Multilocularis; Echinococcosis - complications; Fibrosis; hepatic fibrosis; Liver Cirrhosis - chemically induced; macrophage; Mice; NOTCH signaling; Platelet Aggregation Inhibitors - pharmacology; Signal Transduction
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.202202033R

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. In alveolar echinococcosis, liver fibrosis is one of the characteristic pathological features. Blocking NOTCH signaling increases levels of liver fibrosis in alveolar echinococcosis, downregulating M1 and upregulating M2. NOTCH3/ DLL3 may be the key signaling pathway responsible for this phenomenon.