Neutrophil infiltration regulates clock-gene expression to organize daily hepatic metabolism

Abstract

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 Bmal1 expression in the hepatocyte. Interestingly, mice with neutropenia, defective neutrophil infiltration or lacking elastase were protected against steatosis correlating with lower JNK activation, reduced Bmal1 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 Bmal1 expression in the liver. This study demonstrates that neutrophils contribute to the maintenance of daily hepatic homeostasis through the regulation of the NE/JNK/Bmal1 axis.

The circadian clock and metabolic homeostasis: entangled networks

“…Recent evidence supports an interesting regulatory role of neutrophils in liver rhythms. Reduced neutrophil infiltration, under different experimental conditions, is protective against jetlag and diet-induced liver steatosis in a FGF21-dependent manner [ 281 ]. Sirtuin1 (SIRT1) is an important nutrient-sensing protein that interacts with the molecular clock.…”

Circadian Clock and Liver Cancer

“…Interestingly, this reorganization of liver circadian metabolism is independent of obesity and is mediated by direct effects of the diet [ 25 ]. Recently, our group demonstrated that part of this reprogramming of liver circadian rhythm is caused by the deregulation of neutrophils infiltration in the liver, for instance from diet or jet lag [ 27 ]. Neutrophils show a circadian infiltration into the liver, where they signal hepatocytes through the secretion of the serine protease elastase, synchronizing the circadian clock and liver metabolism.…”

“…The clock gene Rev - erbα activates Cyp7a1 gene expression, possibly through the inhibition of Shp transcription [ 46 ]. We recently demonstrated that, in mice, the liver c-Jun NH 2 -terminal kinases (JNK)1/2 have a circadian regulation in the liver [ 27 ] and control bile acid production; correspondingly, ablation of hepatic JNK1/2 results in bile acid dysregulation and cholestasis [ 47 ]. This alteration in the control of bile acid metabolism also appears in mice lacking the clock gene Per1/2, which present high levels of serum and liver bile acids and liver damage [ 48 ].…”

“…Extrinsic factors, such as non-parenchymal cells, may also affect the liver circadian clock. We have recently published that neutrophils are able to control the liver circadian clock through the activation of hepatic JNKs [ 27 ]. JNKs activate Bmal1 transcription and repress the cycling hepatokine FGF21; both events affect liver lipid metabolism, by activating lipogenesis and reducing the FGF21-metabolic regulatory effect, respectively [ 27 ].…”

“…We have recently published that neutrophils are able to control the liver circadian clock through the activation of hepatic JNKs [ 27 ]. JNKs activate Bmal1 transcription and repress the cycling hepatokine FGF21; both events affect liver lipid metabolism, by activating lipogenesis and reducing the FGF21-metabolic regulatory effect, respectively [ 27 ]. Interestingly, JNKs have a circadian activation in mouse liver [ 20 ], and disruption of hepatic JNKs disrupts bile acid production and results in cholangiocarcinoma [ 47 ].…”