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

IF 4.8 3区 医学 Q1 PHARMACOLOGY & PHARMACY Toxicology Pub Date : 2025-01-17 DOI:10.1016/j.tox.2025.154058
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
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引用次数: 0

摘要

对乙酰氨基酚(APAP)是药物性急性肝损伤(ALI)最常见的诱发因素之一。肝脏免疫细胞对免疫系统激活和炎症级联反应的复杂调节在处理肝损伤和随后的恢复中至关重要。在这项研究中,我们采用了一种综合方法,将我们专有的流式细胞术分析与公开可用的单细胞RNA测序(scRNA-seq)数据集融合在APAP损伤后的各个时间点上,包括APAP中毒小鼠肝组织的时间序列数据。这使我们能够深入研究apap诱导ALI期间T细胞谱的动态。我们的综合分析揭示了apap诱导ALI后不同时期肝内T细胞群的复杂时间变化。值得注意的是,我们观察到apap损伤后肝内CD4+ T细胞持续增加。其中,出现了一种独特的恢复性Cxcr3+组织常驻CD4+ T细胞群。使用中和抗体抑制CXCR3加重apap诱导的肝功能损害和肝细胞死亡。此外,我们发现Cxcr3+组织常驻CD4+ T细胞受到肝内“Lgals9-Cd45”和“CXCL13-Cxcr3”信号通路的严格调控。这些发现强调了CXCR3(一种重要的生物大分子)在减轻apap诱导的ALI中的新保护功能,并可能为针对这种疾病的新治疗策略提供线索。
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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.

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来源期刊
Toxicology
Toxicology 医学-毒理学
CiteScore
7.80
自引率
4.40%
发文量
222
审稿时长
23 days
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.
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