Shen-Xi Ouyang, Yong-Gang Xu, Peng Ding, Yue Long, Zhen Zhang, Si-Jia Sun, Yan Zhang, Hang Yin, Jia-Bao Zhang, Qi Cao, Fu-Ming Shen, Pei Wang, Jian Liu, Dong-Jie Li
{"title":"肝内T细胞的动态分析揭示了急性肝损伤中一组独特的恢复性Cxcr3+组织驻留CD4 T细胞","authors":"Shen-Xi Ouyang, Yong-Gang Xu, Peng Ding, Yue Long, Zhen Zhang, Si-Jia Sun, Yan Zhang, Hang Yin, Jia-Bao Zhang, Qi Cao, Fu-Ming Shen, Pei Wang, Jian Liu, Dong-Jie Li","doi":"10.1016/j.tox.2025.154058","DOIUrl":null,"url":null,"abstract":"<p><p>Acetaminophen (APAP) stands as one of the most prevalent triggers of drug-induced acute liver injury (ALI). The intricate modulation of immune system activation and inflammatory cascades by hepatic immune cells is paramount in managing liver injury and subsequent restoration. In this study, we employed an integrative approach that fused our proprietary flow cytometry analyses across various time points post-APAP injury with publicly available single-cell RNA sequencing (scRNA-seq) datasets, encompassing time-series data from liver tissue of mice subjected to APAP intoxication. This allowed us to delve into the dynamics of T cell profiles during APAP-induced ALI. Our comprehensive analyses unveiled the intricate temporal shifts in intrahepatic T cell populations across different phases following APAP-induced ALI. Notably, we observed a persistent augmentation of intrahepatic CD4<sup>+</sup> T cells post-APAP injury. Amongst these, a distinct population of restorative Cxcr3<sup>+</sup> tissue-resident CD4<sup>+</sup> T cells emerged. Inhibition of CXCR3 using a neutralizing antibody exacerbated APAP-induced liver function impairment and hepatocyte death. Furthermore, we identified that the Cxcr3<sup>+</sup> tissue-resident CD4<sup>+</sup> T cells were tightly regulated by intrahepatic ''Lgals9-Cd45'' and 'CXCL13-Cxcr3' signaling pathways. These discoveries underscore the novel protective function of CXCR3, a vital biological macromolecule, in mitigating APAP-induced ALI, and may shed lights on new therapeutic strategies targeting this condition.</p>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":" ","pages":"154058"},"PeriodicalIF":4.8000,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Dynamic analysis of intrahepatic T cells reveals a unique group of restorative Cxcr3<sup>+</sup> tissue-resident CD4 T cells in acute liver injury.\",\"authors\":\"Shen-Xi Ouyang, Yong-Gang Xu, Peng Ding, Yue Long, Zhen Zhang, Si-Jia Sun, Yan Zhang, Hang Yin, Jia-Bao Zhang, Qi Cao, Fu-Ming Shen, Pei Wang, Jian Liu, Dong-Jie Li\",\"doi\":\"10.1016/j.tox.2025.154058\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Acetaminophen (APAP) stands as one of the most prevalent triggers of drug-induced acute liver injury (ALI). The intricate modulation of immune system activation and inflammatory cascades by hepatic immune cells is paramount in managing liver injury and subsequent restoration. In this study, we employed an integrative approach that fused our proprietary flow cytometry analyses across various time points post-APAP injury with publicly available single-cell RNA sequencing (scRNA-seq) datasets, encompassing time-series data from liver tissue of mice subjected to APAP intoxication. This allowed us to delve into the dynamics of T cell profiles during APAP-induced ALI. Our comprehensive analyses unveiled the intricate temporal shifts in intrahepatic T cell populations across different phases following APAP-induced ALI. Notably, we observed a persistent augmentation of intrahepatic CD4<sup>+</sup> T cells post-APAP injury. Amongst these, a distinct population of restorative Cxcr3<sup>+</sup> tissue-resident CD4<sup>+</sup> T cells emerged. Inhibition of CXCR3 using a neutralizing antibody exacerbated APAP-induced liver function impairment and hepatocyte death. Furthermore, we identified that the Cxcr3<sup>+</sup> tissue-resident CD4<sup>+</sup> T cells were tightly regulated by intrahepatic ''Lgals9-Cd45'' and 'CXCL13-Cxcr3' signaling pathways. These discoveries underscore the novel protective function of CXCR3, a vital biological macromolecule, in mitigating APAP-induced ALI, and may shed lights on new therapeutic strategies targeting this condition.</p>\",\"PeriodicalId\":23159,\"journal\":{\"name\":\"Toxicology\",\"volume\":\" \",\"pages\":\"154058\"},\"PeriodicalIF\":4.8000,\"publicationDate\":\"2025-01-17\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Toxicology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.tox.2025.154058\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Toxicology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.tox.2025.154058","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
Dynamic analysis of intrahepatic T cells reveals a unique group of restorative Cxcr3+ tissue-resident CD4 T cells in acute liver injury.
Acetaminophen (APAP) stands as one of the most prevalent triggers of drug-induced acute liver injury (ALI). The intricate modulation of immune system activation and inflammatory cascades by hepatic immune cells is paramount in managing liver injury and subsequent restoration. In this study, we employed an integrative approach that fused our proprietary flow cytometry analyses across various time points post-APAP injury with publicly available single-cell RNA sequencing (scRNA-seq) datasets, encompassing time-series data from liver tissue of mice subjected to APAP intoxication. This allowed us to delve into the dynamics of T cell profiles during APAP-induced ALI. Our comprehensive analyses unveiled the intricate temporal shifts in intrahepatic T cell populations across different phases following APAP-induced ALI. Notably, we observed a persistent augmentation of intrahepatic CD4+ T cells post-APAP injury. Amongst these, a distinct population of restorative Cxcr3+ tissue-resident CD4+ T cells emerged. Inhibition of CXCR3 using a neutralizing antibody exacerbated APAP-induced liver function impairment and hepatocyte death. Furthermore, we identified that the Cxcr3+ tissue-resident CD4+ T cells were tightly regulated by intrahepatic ''Lgals9-Cd45'' and 'CXCL13-Cxcr3' signaling pathways. These discoveries underscore the novel protective function of CXCR3, a vital biological macromolecule, in mitigating APAP-induced ALI, and may shed lights on new therapeutic strategies targeting this condition.
期刊介绍:
Toxicology is an international, peer-reviewed journal that publishes only the highest quality original scientific research and critical reviews describing hypothesis-based investigations into mechanisms of toxicity associated with exposures to xenobiotic chemicals, particularly as it relates to human health. In this respect "mechanisms" is defined on both the macro (e.g. physiological, biological, kinetic, species, sex, etc.) and molecular (genomic, transcriptomic, metabolic, etc.) scale. Emphasis is placed on findings that identify novel hazards and that can be extrapolated to exposures and mechanisms that are relevant to estimating human risk. Toxicology also publishes brief communications, personal commentaries and opinion articles, as well as concise expert reviews on contemporary topics. All research and review articles published in Toxicology are subject to rigorous peer review. Authors are asked to contact the Editor-in-Chief prior to submitting review articles or commentaries for consideration for publication in Toxicology.