Neutrophil infiltration regulates clock-gene expression to organize daily hepatic metabolism
| Autor: | Norman J. Kennedy, Cintia Folgueira, Magdalena Leiva, Jorge L Torres, Lourdes Hernández-Cosido, Bárbara González-Terán, Luis Leiva-Vega, Ivana Nikolic, Miguel Marcos, Noelia A-Gonzalez, Andrés Hidalgo, Rui Benedito, Alfonso Mora, Irene Ruiz-Garrido, Aránzazu Pintor-Chocano, Ainoa Caballero-Molano, Nuria Matesanz, Elena Rodríguez, Roger J. Davis, Daniel Beiroa, Beatriz Cicuéndez, Macarena Fernández-Chacón, María Crespo, Guadalupe Sabio, Rubén Nogueiras, Antonia Tomás-Loba |
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| Přispěvatelé: | Fundación Lilly, Horizon 2020, Howard Hughes Medical Institute, European Research Council, Fundación BBVA, Ministerio de Asuntos Económicos y Transformación Digital (España), Comunidad de Madrid, Fundación Científica AECC, National Institutes of Health (United States), Gobierno de Castilla y León, Ministerio de Ciencia, Innovación y Universidades (España), Fundación ProCNIC, Instituto de Salud Carlos III - ISCIII, Unión Europea. Comisión Europea. H2020, Comunidad de Madrid (España), Asociación Española Contra el Cáncer, National Institutes of Health (Estados Unidos), Junta de Castilla y León (España), Instituto de Salud Carlos III |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
FGF21 Mouse MAP Kinase Kinase 4 Neutrophils CLOCK Proteins Mice 0302 clinical medicine Immunology and Inflammation steatosis Biology (General) Cells Cultured Regulation of gene expression biology Kinase Chemistry General Neuroscience Elastase General Medicine Cell biology Circadian Rhythm CLOCK medicine.anatomical_structure 030220 oncology & carcinogenesis Hepatocyte Neutrophil elastase Medicine neutrophil elastase Research Article circadian rhythm Neutropenia QH301-705.5 Science Mice Transgenic General Biochemistry Genetics and Molecular Biology 03 medical and health sciences medicine Animals Humans Inflammation General Immunology and Microbiology Cell Biology Fibroblast Growth Factors 030104 developmental biology Gene Expression Regulation biology.protein Hepatocytes JNK |
| Zdroj: | Repisalud Instituto de Salud Carlos III (ISCIII) eLife eLife, Vol 9 (2020) |
| Popis: | 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. eLife digest Every day, the body's biological processes work to an internal clock known as the circadian rhythm. This rhythm is controlled by ‘clock genes’ that are switched on or off by daily physical and environmental cues, such as changes in light levels. These daily rhythms are very finely tuned, and disturbances can lead to serious health problems, such as diabetes or high blood pressure. The ability of the body to cycle through the circadian rhythm each day is heavily influenced by the clock of one key organ: the liver. This organ plays a critical role in converting food and drink into energy. There is evidence that neutrophils – white blood cells that protect the body by being the first response to inflammation – can influence how the liver performs its role in obese people, by for example, releasing a protein called elastase. Additionally, the levels of neutrophils circulating in the blood change following a daily pattern. Crespo, González-Terán et al. wondered whether neutrophils enter the liver at specific times of the day to control liver’s daily rhythm. Crespo, González-Terán et al. revealed that neutrophils visit the liver in a pattern that peaks when it gets light and dips when it gets dark by counting the number of neutrophils in the livers of mice at different times of the day. During these visits, neutrophils secreted elastase, which activated a protein called JNK in the cells of the mice’s liver. This subsequently blocked the activity of another protein, FGF21, which led to the activation of the genes that allow cells to make fat molecules for storage. JNK activation also switched on the clock gene, Bmal1, ultimately causing fat to build up in the mice’s liver. Crespo, González-Terán et al. also found that, in samples from human livers, the levels of elastase, the activity of JNK, and whether the Bmal1 gene was switched on were tightly linked. This suggests that neutrophils may be controlling the liver’s rhythm in humans the same way they do in mice. Overall, this research shows that neutrophils can control and reset the liver's daily rhythm using a precisely co-ordinated series of molecular changes. These insights into the liver's molecular clock suggest that elastase, JNK and BmaI1 may represent new therapeutic targets for drugs or smart medicines to treat metabolic diseases such as diabetes or high blood pressure. |
| Databáze: | OpenAIRE |
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