期刊
CELLULAR & MOLECULAR IMMUNOLOGY
卷 20, 期 2, 页码 143-157出版社
CHIN SOCIETY IMMUNOLOGY
DOI: 10.1038/s41423-022-00966-y
关键词
APAP-ALI; IFN-I; Macrophage polarization; scRNA-seq; STAT2 T403 phosphorylation; CSF1+neutrophil
类别
We investigated the role of IFN-I in the myeloid compartment during acetaminophen overdose-induced acute liver injury (APAP-ALI) through single-cell RNA sequencing. We identified IFN-I-dependent transcriptional programs that promote efficient liver repair by facilitating the maturation of restorative macrophages. Our findings suggest the therapeutic potential of IFN-I in the treatment of APAP-ALI.
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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