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Type I interferon signaling facilitates resolution of acute liver injury by priming macrophage polarization

Cellular & Molecular Immunology volume 20, pages 143–157 (2023)Cite this article

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Abstract

Due to their broad functional plasticity, myeloid cells contribute to both liver injury and recovery during acetaminophen overdose-induced acute liver injury (APAP-ALI). A comprehensive understanding of cellular diversity and intercellular crosstalk is essential to elucidate the mechanisms and to develop therapeutic strategies for APAP-ALI treatment. Here, we identified the function of IFN-I in the myeloid compartment during APAP-ALI. Utilizing single-cell RNA sequencing, we characterized the cellular atlas and dynamic progression of liver CD11b+ cells post APAP-ALI in WT and STAT2 T403A mice, which was further validated by immunofluorescence staining, bulk RNA-seq, and functional experiments in vitro and in vivo. We identified IFN-I-dependent transcriptional programs in a three-way communication pathway that involved IFN-I synthesis in intermediate restorative macrophages, leading to CSF-1 production in aging neutrophils that ultimately enabled Trem2+ restorative macrophage maturation, contributing to efficient liver repair. Overall, we uncovered the heterogeneity of hepatic myeloid cells in APAP-ALI at single-cell resolution and the therapeutic potential of IFN-I in the treatment of APAP-ALI.

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Funding

This work was supported by the Key R&D Program of Shandong Province (2020CXGC010503), Shandong Provincial Key Laboratory Platform Project (2021ZDSYS11), and Major Program of National Natural Science Foundation of China (81991525).

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Authors and Affiliations

  1. Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China

    Qiaoling Song, Xiaohan Xu, Zhan Zhao, Chenyang Zhao & Jinbo Yang

  2. Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA

    Shyamasree Datta, Paul Pavicic, Ganes Sen & Thomas Hamilton

  3. Lars Bolund Institute of Regenerative Medicine, Qingdao-Europe Advanced Institute for Life Sciences, BGI-Qingdao, BGI-Shenzhen, Shenzhen, China

    Xue Liang, Peng Han, Yating Qin, Yingying Zhang & Yonglun Luo

  4. Innovation Center of Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China

    Xiaonan Zhang, Shan Liu, Jun Zhao, Yuting Xu, Jing Xu, Lihong Wu, Zhihua Wu, Minghui Zhang, Chenyang Zhao & Jinbo Yang

  5. Department of Radiation, Affiliated Hospital of Qingdao University, Qingdao, China

    Yuanyuan Zhao, Peng Jiang & Wei Li

  6. Department of Urology, Yantai Yuhuangding Hospital, Yantai, China

    Chunhua Lin

  7. Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA

    Yuxin Wang & George R. Stark

Authors
  1. Qiaoling Song
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  2. Shyamasree Datta
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Contributions

TH, CZ and JY directed all aspects of the project. QS, SD, XX, PP, YZhao, SL, ZZ, PH, PJ, YQ, WL, JZ, YX, JX, ZW, LW, MZ and YZhang performed the experiments. XL, QS and CY analyzed the seq data with significant contributions from XL in data visualization. XZ and CL discussed the clinical features of liver injury and reviewed the pathology sections. QS, CZ, JY and TH wrote the manuscript. YW, GS, YL and GRS read the manuscript and provided useful comments.

Corresponding authors

Correspondence to Chenyang Zhao, Thomas Hamilton or Jinbo Yang.

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Song, Q., Datta, S., Liang, X. et al. Type I interferon signaling facilitates resolution of acute liver injury by priming macrophage polarization. Cell Mol Immunol 20, 143–157 (2023). https://doi.org/10.1038/s41423-022-00966-y

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Keywords

  • APAP-ALI
  • IFN-I
  • Macrophage polarization
  • scRNA-seq
  • STAT2 T403 phosphorylation
  • CSF1+ neutrophil

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