Program in Molecular Medicine; Davis Lab
Biochemical Phenomena, Metabolism, and Nutrition | Cell Biology | Cellular and Molecular Physiology | Hemic and Immune Systems | Immunology and Infectious Disease | Physiological Processes
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.
JNK, cell biology, circadian rhythm, immunology, inflammation, mouse, neutrophil elastase, steatosis, liver metabolism
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Copyright © 2020, Crespo et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
DOI of Published Version
Crespo M, Gonzalez-Teran B, Nikolic I, Mora A, Folgueira C, Rodríguez E, Leiva-Vega L, Pintor-Chocano A, Fernández-Chacón M, Ruiz-Garrido I, Cicuéndez B, Tomás-Loba A, A-Gonzalez N, Caballero-Molano A, Beiroa D, Hernández-Cosido L, Torres JL, Kennedy NJ, Davis RJ, Benedito R, Marcos M, Nogueiras R, Hidalgo A, Matesanz N, Leiva M, Sabio G. Neutrophil infiltration regulates clock-gene expression to organize daily hepatic metabolism. Elife. 2020 Dec 8;9:e59258. doi: 10.7554/eLife.59258. PMID: 33287957; PMCID: PMC7723411. Link to article on publisher's site
Crespo M, Kennedy NJ, Davis RJ, Matesanz N, Leiva M, Sabio G. (2020). Neutrophil infiltration regulates clock-gene expression to organize daily hepatic metabolism. University of Massachusetts Medical School Faculty Publications. https://doi.org/10.7554/eLife.59258. Retrieved from https://escholarship.umassmed.edu/faculty_pubs/1886
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