两种饮食诱导的非酒精性脂肪性肝炎相关肝纤维化小鼠模型中自然杀伤 T 细胞作用的比较研究。
A comparative study on roles of natural killer T cells in two diet-induced non-alcoholic steatohepatitis-related fibrosis in mice.
机构信息
Department of Gastroenterology and Hepatology, The General Hospital of Western Theater Command, Chengdu, China.
Department of Gastroenterology and Hepatology, Shanghai Tongji Hospital, Shanghai Tongji University, Shanghai, China.
出版信息
Ann Med. 2022 Dec;54(1):2233-2245. doi: 10.1080/07853890.2022.2108894.
BACKGROUND
Immune responses are important in the progression of non-alcoholic fatty liver disease (NAFLD). Natural killer T (NKT) cells are main components of the innate immune system that modulate immunity. However, the role of NKT cells in NAFLD remains controversial.
OBJECTIVE
We aimed to investigate the role of NKT cells in non-alcoholic steatohepatitis (NASH)-related fibrosis in fast food diet (FFD)- and methionine choline-deficient (MCD) diet-induced mouse models.
METHODS
Hepatic NKT cells were analysed in wild-type (WT) and CD1d-/- mice fed FFD or MCD diets. Hepatic pathology, cytokine profiles and liver fibrosis were evaluated. Furthermore, the effect of chronic administration of α-galactosylceramide (α-GalCer) on liver fibrosis was investigated in both FFD- and MCD-treated mice.
RESULTS
FFD induced a significant depletion of hepatic NKT cells, thus leading to mild to moderate NASH and early-stage fibrosis, while mice fed MCD diets developed severe liver inflammation and progressive fibrosis without a significant change in hepatic NKT cell abundance. FFD induced a similar liver fibrogenic response in CD1d-/- and WT mice, while MCD induced a higher hepatic mRNA expression of Col1α1 and TIMP1 as well as relative fibrosis density in CD1d-/- mice than WT mice (31.8 . 16.3, = .039; 40.0 . 22.6, = .019; 2.24 . 1.59, = .036). Chronic administration of α-GalCer induced a higher hepatic mRNA expression of TIMP1 in MCD-treated mice than controls (36.7 14.9, = .005).
CONCLUSION
NKT cells have protective roles in NAFLD as the disease progresses. During diet-induced steatosis, mild to moderate NASH and the early stage of fibrosis, hepatic NKT cells are relatively depleted, leading to a proinflammatory status. In severe NASH and the advanced stage of liver fibrosis, NKT cells play a role in inhibiting the NASH-related fibrogenic response. Chronic administration of α-GalCer induces NKT cell anergy and tolerance, which may play a role in promoting the liver fibrogenic response.
背景
免疫反应在非酒精性脂肪性肝病（NAFLD）的进展中很重要。自然杀伤 T（NKT）细胞是调节免疫的固有免疫系统的主要组成部分。然而，NKT 细胞在 NAFLD 中的作用仍存在争议。
目的
我们旨在研究 NKT 细胞在快餐饮食（FFD）和蛋氨酸胆碱缺乏（MCD）饮食诱导的小鼠模型中与非酒精性脂肪性肝炎（NASH）相关纤维化中的作用。
方法
在给予 FFD 或 MCD 饮食的野生型（WT）和 CD1d-/-小鼠中分析肝 NKT 细胞。评估肝病理学、细胞因子谱和肝纤维化。此外，还研究了慢性给予α-半乳糖神经酰胺（α-GalCer）对 FFD 和 MCD 治疗小鼠肝纤维化的影响。
结果
FFD 诱导肝 NKT 细胞明显耗竭，导致轻度至中度 NASH 和早期纤维化，而给予 MCD 饮食的小鼠则发生严重的肝炎症和进行性纤维化，而肝 NKT 细胞丰度无明显变化。FFD 在 CD1d-/-和 WT 小鼠中诱导相似的肝纤维发生反应，而 MCD 在 CD1d-/-小鼠中诱导更高的肝 Col1α1 和 TIMP1 mRNA 表达以及相对纤维化密度（31.8±16.3，=0.039；40.0±22.6，=0.019；2.24±1.59，=0.036）。慢性给予α-GalCer 在 MCD 治疗的小鼠中诱导更高的肝 TIMP1 mRNA 表达（36.7±14.9，=0.005）。
结论
随着疾病的进展，NKT 细胞在 NAFLD 中具有保护作用。在饮食诱导的脂肪变性、轻度至中度 NASH 和早期纤维化期间，肝 NKT 细胞相对耗竭，导致炎症状态。在严重的 NASH 和晚期肝纤维化中，NKT 细胞在抑制 NASH 相关纤维发生反应中起作用。慢性给予α-GalCer 诱导 NKT 细胞失能和耐受，可能在促进肝纤维发生反应中起作用。
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