University of Massachusetts Medical School Faculty Publications

UMMS Affiliation

Program in Molecular Medicine; Davis Lab

Publication Date

2020-12-08

Document Type

Article

Disciplines

Biochemical Phenomena, Metabolism, and Nutrition | Cell Biology | Cellular and Molecular Physiology | Hemic and Immune Systems | Immunology and Infectious Disease | Physiological Processes

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.

Keywords

JNK, cell biology, circadian rhythm, immunology, inflammation, mouse, neutrophil elastase, steatosis, liver metabolism

Rights and Permissions

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

10.7554/eLife.59258

Source

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

Comments

Full author list omitted for brevity. For the full list of authors, see article.

Related Resources

Link to Article in PubMed

Journal/Book/Conference Title

eLife

PubMed ID

33287957

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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