Hepatology communications · 2025
Multiple cell-type interactions drive invariant NKT cell hepatitis.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Tan Jiaxin, Ji Longshan, Li Qian, Guo Ruowen, Hao Yawen, Xiao Peng, Zai Qiuhong, Zhang Xuewei, Gao Yating, Zhang Xin, Fang Miao, Gao Yanhang, Zhao Weidong, He Yong, Gao Yueqiu, Li Man
Аннотация
BACKGROUND: α-Galactosylceramide (α-Galcer), a specific ligand for invariant natural killer T (NKT) cell activation, has been actively investigated in clinical trials such as antitumor therapy; however, treatment with α-Galcer is well known to induce acute hepatitis due to enriched NKT cells in the liver. The molecular mechanisms underlying NKT-mediated hepatitis still remain obscure. The object of this study was to investigate whether and how myeloid cells affect NKT-mediated hepatitis.
METHODS: α-Galcer-induced NKT hepatitis was used in this study. microRNA-223 (miR-223) and neutrophil cytosolic factor 1 (Ncf1)-deficent mice were generated and subjected to α-Galcer-induced NKT hepatitis.
RESULTS: In this study, we demonstrated that α-Galcer-induced NKT cell activation resulted in neutrophil and monocyte-derived macrophage accumulation in the liver. Importantly, serum levels of several hepatic myeloid cell infiltration-related cytokines and chemokines were significantly elevated after α-Galcer administration. Among these myeloid cells, blockade of neutrophil or macrophage migration through using different inhibitors of (C-X-C Motif) receptor 2, (C-C motif) receptor 2, and (C-C motif) receptor 5 signaling ameliorated α-Galcer-induced liver injury, mainly due to the decrease of reactive oxygen species production and inflammation. Depletion of neutrophils reduced α-Galcer-induced liver injury and hepatitis. Interestingly, genetic deletion of neutrophil-specific miR-223 markedly enhanced while Ncf1 deficiency significantly ameliorated liver inflammation and oxidative damage caused by α-Galcer.
CONCLUSIONS: Neutrophil and macrophage infiltration through multiple inflammatory mediators is required for NKT cell activation-induced hepatitis, which sheds light on the myeloid cell infiltration-related molecular mechanisms of NKT cell-mediated liver injury. Our study may provide a novel therapeutical strategy for the treatment of NKT cell hepatitis.
METHODS: α-Galcer-induced NKT hepatitis was used in this study. microRNA-223 (miR-223) and neutrophil cytosolic factor 1 (Ncf1)-deficent mice were generated and subjected to α-Galcer-induced NKT hepatitis.
RESULTS: In this study, we demonstrated that α-Galcer-induced NKT cell activation resulted in neutrophil and monocyte-derived macrophage accumulation in the liver. Importantly, serum levels of several hepatic myeloid cell infiltration-related cytokines and chemokines were significantly elevated after α-Galcer administration. Among these myeloid cells, blockade of neutrophil or macrophage migration through using different inhibitors of (C-X-C Motif) receptor 2, (C-C motif) receptor 2, and (C-C motif) receptor 5 signaling ameliorated α-Galcer-induced liver injury, mainly due to the decrease of reactive oxygen species production and inflammation. Depletion of neutrophils reduced α-Galcer-induced liver injury and hepatitis. Interestingly, genetic deletion of neutrophil-specific miR-223 markedly enhanced while Ncf1 deficiency significantly ameliorated liver inflammation and oxidative damage caused by α-Galcer.
CONCLUSIONS: Neutrophil and macrophage infiltration through multiple inflammatory mediators is required for NKT cell activation-induced hepatitis, which sheds light on the myeloid cell infiltration-related molecular mechanisms of NKT cell-mediated liver injury. Our study may provide a novel therapeutical strategy for the treatment of NKT cell hepatitis.