Centro Nacional de Investigaciones Cardiovasculares Carlos (CNIC), Madrid, Spain.
CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain.
Elife. 2020 Dec 8;9:e59258. doi: 10.7554/eLife.59258.
Liver metabolism follows diurnal fluctuations through the modulation of molecular clock genes. Disruption of this molecular clock can result in metabolic disease but its potential regulation by immune cells remains unexplored. Here, we demonstrated that in steady state, neutrophils infiltrated the mouse liver following a circadian pattern and regulated hepatocyte clock-genes by neutrophil elastase (NE) secretion. NE signals through c-Jun NH2-terminal kinase (JNK) inhibiting fibroblast growth factor 21 (FGF21) and activating expression in the hepatocyte. Interestingly, mice with neutropenia, defective neutrophil infiltration or lacking elastase were protected against steatosis correlating with lower JNK activation, reduced and increased FGF21 expression, together with decreased lipogenesis in the liver. Lastly, using a cohort of human samples we found a direct correlation between JNK activation, NE levels and expression in the liver. This study demonstrates that neutrophils contribute to the maintenance of daily hepatic homeostasis through the regulation of the NE/JNK/ axis.
肝脏代谢通过分子钟基因的调节呈现昼夜波动。这种分子钟的破坏可能导致代谢疾病，但免疫细胞对其的潜在调节作用仍未被探索。在这里，我们证明在稳态下，中性粒细胞按照昼夜节律模式浸润小鼠肝脏，并通过中性粒细胞弹性蛋白酶 (NE) 的分泌来调节肝细胞时钟基因。NE 通过 c-Jun NH2-末端激酶 (JNK) 信号传导抑制成纤维细胞生长因子 21 (FGF21) 并激活肝细胞中的 表达。有趣的是，中性粒细胞减少症、中性粒细胞浸润缺陷或缺乏弹性蛋白酶的小鼠可预防脂肪变性，这与 JNK 激活降低、减少 和增加 FGF21 表达以及肝脏中脂肪生成减少有关。最后，使用一组人类样本，我们发现肝脏中 JNK 激活、NE 水平和 表达之间存在直接相关性。这项研究表明，中性粒细胞通过调节 NE/JNK/ 轴来促进肝脏日常内稳态的维持。
