Advertisement

Targeting Notch1-YAP circuit reprograms macrophage polarization and alleviates acute liver injury in mice

  • Author Footnotes
    # These authors contributed equally to this work.
    Yan Yang
    Footnotes
    # These authors contributed equally to this work.
    Affiliations
    Department of Physiology, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, China

    Tissue Engineering and Organ Manufacturing (TEOM) Lab, Department of Biomedical Engineering, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, China
    Search for articles by this author
  • Author Footnotes
    # These authors contributed equally to this work.
    Ming Ni
    Footnotes
    # These authors contributed equally to this work.
    Affiliations
    Hepatobiliary Center of The First Affiliated Hospital, Nanjing Medical University; Research Unit of Liver Transplantation and Transplant Immunology, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China
    Search for articles by this author
  • Ruobin Zong
    Affiliations
    Department of Physiology, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, China
    Search for articles by this author
  • Mengxue Yu
    Affiliations
    Department of Physiology, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, China
    Search for articles by this author
  • Yishuang Sun
    Affiliations
    Department of Physiology, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, China
    Search for articles by this author
  • Jiahui Li
    Affiliations
    Department of Physiology, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, China
    Search for articles by this author
  • Pu Chen
    Correspondence
    Correspondence: Pu Chen, PhD. Tissue Engineering and Organ Manufacturing (TEOM) Lab, Department of Biomedical Engineering, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, China.
    Affiliations
    Tissue Engineering and Organ Manufacturing (TEOM) Lab, Department of Biomedical Engineering, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, China
    Search for articles by this author
  • Changyong Li
    Correspondence
    Correspondence: Pu Chen, PhD. Tissue Engineering and Organ Manufacturing (TEOM) Lab, Department of Biomedical Engineering, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, China.Correspondence: Changyong Li, MD, PhD. Department of Physiology, Wuhan University School of Basic Medical Sciences, 115 Donghu Road, Wuhan 430071, China. [email protected]
    Affiliations
    Department of Physiology, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, China
    Search for articles by this author
  • Author Footnotes
    # These authors contributed equally to this work.
Open AccessPublished:January 24, 2023DOI:https://doi.org/10.1016/j.jcmgh.2023.01.002
      This paper is only available as a PDF. To read, Please Download here.

      Abstract

      Background & Aims

      Hepatic immune system disorder plays a critical role in the pathogenesis of acute liver injury. The intrinsic signaling mechanisms responsible for dampening excessive activation of liver macrophages are not completely understood. The Notch and Hippo-YAP signaling pathways have been implicated in immune homeostasis. In this study, we investigated the interactive cell signaling networks of Notch1/YAP pathway during acute liver injury.

      Methods

      Myeloid-specific Notch1 knockout (Notch1M-KO) mice and the floxed Notch1 (Notch1FL/FL) mice were subjected to lipopolysaccharide (LPS)/D-galactosamine (D-GalN) toxicity. Some mice were injected via the tail vein with bone marrow-derived macrophages transfected with lentivirus-expressing YAP. Some mice were injected with YAP siRNA using an in vivo mannose-mediated delivery system.

      Results

      We found that the activated Notch1 and YAP signaling in liver macrophages were closely related to LPS/D-GalN-induced acute liver injury. Macrophage/neutrophil infiltration, pro-inflammatory mediators, and hepatocellular apoptosis were markedly ameliorated in Notch1M-KO mice. Importantly, myeloid Notch1 deficiency depressed YAP signaling and facilitated M2 macrophage polarization in the injured liver. Furthermore, YAP overexpression in Notch1M-KO livers exacerbated liver damage and shifted macrophage polarization toward the M1 phenotype. Mechanistically, macrophage Notch1 signaling could transcriptionally activate YAP gene expression. Reciprocally, YAP transcriptionally upregulated the Notch ligand Jagged1 gene expression and was essential for Notch1-mediated macrophage polarization. Finally, dual inhibition of Notch1 and YAP in macrophages further promoted M2 polarization and alleviated liver damage.

      Conclusions

      Our findings underscore a novel molecular insight into the Notch1-YAP circuit for controlling macrophage polarization in acute liver injury, raising the possibility of targeting macrophage Notch1-YAP circuit as an effective strategy for liver inflammation-related diseases.

      Graphical abstract

      Keywords

      Abbreviations:

      ALT (alanine aminotransferase), Arg1 (arginase 1), ASK1 (apoptosis signal-regulating kinase 1), AST (aspartate aminotransferase), BMDMs (bone marrow-derived macrophages), CTGF (connective tissue growth factor), CXCL-1 (C-X-C motif chemokine ligand 1), Cyr61 (cysteine-rich angiogenic inducer 61), D-GalN (D-galactosamine), Hes1 (Hairy enhancer of split), HMGB1 (high mobility group box 1), IL-1β (interleukin-1β), IL-6 (interleukin-6), IL-10 (interleukin-10), TGF-β (transforming growth factor-β), iNOS (inducible nitric oxide synthase), JAG1 (Jagged1), LPS (lipopolysaccharide), MCP1 (monocyte chemoattractant protein-1), NICD (Notch intracellular domain), TNF-α (tumor necrosis factor α), YAP (Yes-associated protein)