Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/13249
Neutrophil infiltration regulates clock-gene expression to organize daily hepatic metabolism.
Crespo-Ruiz, Maria CNIC | Gonzalez-Teran, Barbara CNIC | Nikolic, Ivana CNIC | Mora, Alfonso CNIC | Folgueira, Cintia | Rodriguez, Elena CNIC | Leiva-Vega, Luis CNIC | Pintor-Chocano, Aranzazu | Fernandez-Chacon, Macarena CNIC | Ruiz-Garrido, Irene | Cicuendez, Beatriz | Tomas-Loba, Antonia CNIC | Alonso-Gonzalez, Noelia CNIC | Caballero-Molano, Ainoa | Beiroa, Daniel | Hernandez-Cosido, Lourdes | Torres, Jorge L | Kennedy, Norman J | Davis, Roger J | Benedito, Rui CNIC | Marcos, Miguel | Nogueiras, Ruben | Hidalgo, Andres CNIC | Matesanz, Nuria CNIC | Leiva, Magdalena CNIC | Sabio, Guadalupe CNIC
Elife. 2020; 9:e59258
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.
Animals | CLOCK Proteins | Cells, Cultured | Circadian Rhythm | Fibroblast Growth Factors | Gene Expression Regulation | Hepatocytes | Humans | Inflammation | MAP Kinase Kinase 4 | Mice | Mice, Transgenic | Neutropenia | Neutrophils