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

María Crespo; Barbara Gonzaiez-Teran; Ivana Nikolic; Alfonso Mora; Cintia Folgueira; Elena Rodríguez; Luis Leiva-Vega; Aránzazu Pintor-Chocano; Macarena Fernandez-Chacón; Irene Ruiz-Garrido; Beatriz Cicuéndez; Antonia Tomás-Loba; Noelia A-Gonzalez; Ainoa Caballero-Molano; Daniel Beiroa; Lourdes Hernández-Cosido; Jorge L. Torres; Norman J. Kennedy; Roger J. Davis; Rui Benedito; Miguel Marcos; Ruben Nogueiras; Andrés Hidalgo; Nuria Matesanz; Magdalena Leiva; Guadalupe Sabio

doi:10.7554/eLife.59258

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

María Crespo, Barbara Gonzaiez-Teran, Ivana Nikolic, Alfonso Mora, Cintia Folgueira, Elena Rodríguez, Luis Leiva-Vega, Aránzazu Pintor-Chocano, Macarena Fernandez-Chacón, Irene Ruiz-Garrido, Beatriz Cicuéndez, Antonia Tomás-Loba, Noelia A-Gonzalez, Ainoa Caballero-Molano, Daniel Beiroa, Lourdes Hernández-Cosido, Jorge L. Torres, Norman J. Kennedy, Roger J. Davis, Rui BeneditoMiguel Marcos, Ruben Nogueiras, Andrés Hidalgo, Nuria Matesanz, Magdalena Leiva, Guadalupe Sabio

Research output: Contribution to journal › Article › peer-review

32 Scopus citations

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

Original language	English
Article number	e59258
Pages (from-to)	1-25
Number of pages	25
Journal	eLife
Volume	9
DOIs	https://doi.org/10.7554/eLife.59258
State	Published - Dec 2020
Externally published	Yes

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Crespo, M., Gonzaiez-Teran, B., Nikolic, I., Mora, A., Folgueira, C., Rodríguez, E., Leiva-Vega, L., Pintor-Chocano, A., Fernandez-Chacón, M., Ruiz-Garrido, I., Cicuéndez, B., Tomás-Loba, A., A-Gonzalez, N., Caballero-Molano, A., Beiroa, D., Hernández-Cosido, L., Torres, J. L., Kennedy, N. J., Davis, R. J., ... Sabio, G. (2020). Neutrophil infiltration regulates clock-gene expression to organize daily hepatic metabolism. eLife, 9, 1-25. Article e59258. https://doi.org/10.7554/eLife.59258

@article{2eccf471bb574491bbc66440e418e226,

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

author = "Mar{\'i}a Crespo and Barbara Gonzaiez-Teran and Ivana Nikolic and Alfonso Mora and Cintia Folgueira and Elena Rodr{\'i}guez and Luis Leiva-Vega and Ar{\'a}nzazu Pintor-Chocano and Macarena Fernandez-Chac{\'o}n and Irene Ruiz-Garrido and Beatriz Cicu{\'e}ndez and Antonia Tom{\'a}s-Loba and Noelia A-Gonzalez and Ainoa Caballero-Molano and Daniel Beiroa and Lourdes Hern{\'a}ndez-Cosido and Torres, {Jorge L.} and Kennedy, {Norman J.} and Davis, {Roger J.} and Rui Benedito and Miguel Marcos and Ruben Nogueiras and Andr{\'e}s Hidalgo and Nuria Matesanz and Magdalena Leiva and Guadalupe Sabio",

note = "Publisher Copyright: {\textcopyright} Crespo et al.",

year = "2020",

month = dec,

doi = "10.7554/eLife.59258",

language = "English",

volume = "9",

pages = "1--25",

journal = "eLife",

issn = "2050-084X",

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Crespo, M, Gonzaiez-Teran, B, Nikolic, I, Mora, A, Folgueira, C, Rodríguez, E, Leiva-Vega, L, Pintor-Chocano, A, Fernandez-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 2020, 'Neutrophil infiltration regulates clock-gene expression to organize daily hepatic metabolism', eLife, vol. 9, e59258, pp. 1-25. https://doi.org/10.7554/eLife.59258

TY - JOUR

T1 - Neutrophil infiltration regulates clock-gene expression to organize daily hepatic metabolism

AU - Crespo, María

AU - Gonzaiez-Teran, Barbara

AU - Nikolic, Ivana

AU - Mora, Alfonso

AU - Folgueira, Cintia

AU - Rodríguez, Elena

AU - Leiva-Vega, Luis

AU - Pintor-Chocano, Aránzazu

AU - Fernandez-Chacón, Macarena

AU - Ruiz-Garrido, Irene

AU - Cicuéndez, Beatriz

AU - Tomás-Loba, Antonia

AU - A-Gonzalez, Noelia

AU - Caballero-Molano, Ainoa

AU - Beiroa, Daniel

AU - Hernández-Cosido, Lourdes

AU - Torres, Jorge L.

AU - Kennedy, Norman J.

AU - Davis, Roger J.

AU - Benedito, Rui

AU - Marcos, Miguel

AU - Nogueiras, Ruben

AU - Hidalgo, Andrés

AU - Matesanz, Nuria

AU - Leiva, Magdalena

AU - Sabio, Guadalupe

PY - 2020/12

Y1 - 2020/12

N2 - 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 Bmall expression in the hepatocyte. Interestingly, mice with neutropenia, defective neutrophil infiltration or lacking elastase were protected against steatosis correlating with lower JNK activation, reduced Bmall 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 Bmall expression in the liver. This study demonstrates that neutrophils contribute to the maintenance of daily hepatic homeostasis through the regulation of the NE/JNK/BmaH axis.

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

UR - http://www.scopus.com/inward/record.url?scp=85097483099&partnerID=8YFLogxK

U2 - 10.7554/eLife.59258

DO - 10.7554/eLife.59258

M3 - Article

C2 - 33287957

AN - SCOPUS:85097483099

SN - 2050-084X

VL - 9

SP - 1

EP - 25

JO - eLife

JF - eLife

M1 - e59258

ER -

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

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