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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
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)Article info
Publication history
Accepted:
January 17,
2023
Received in revised form:
January 15,
2023
Received:
July 15,
2022
Publication stage
In Press Journal Pre-ProofFootnotes
Grant Support: The National Key Research and Development Program of China (No.2018YFA0109000), the Wuhan Municipal Science and Technology Bureau (2020020601012210), and the Natural Science Foundation of Hubei Province (2017CFB620).
SUMMARY
Liver macrophages are highly plastic and adapt their phenotype according to the signals derived from the hepatic microenvironment. In this study, we identify the Notch1-YAP circuit as a key regulator of macrophage polarization and liver inflammation.
Identification
Copyright
© 2023 The Authors. Published by Elsevier Inc. on behalf of the AGA Institute.
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