at the CNIC

Category: Publications (Page 1 of 6)

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

María Crespo, Barbara Gonzalez-Teran, Ivana Nikolic, Alfonso Mora, Cintia Folgueira, Elena Rodríguez, Luis Leiva-Vega, Aránzazu Pintor-Chocano, Macarena Fernández-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.

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.

3-D image of liver section showing the distribution on infiltrated neutrophils in red (Image: Magdalena Leiva).

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.

Brain JNK and metabolic disease

Rubén Nogueiras & Guadalupe Sabio.

Obesity, which has long since reached epidemic proportions worldwide, is associated with long-term stress to a variety of organs and results in diseases including type 2 diabetes. In the brain, overnutrition induces hypothalamic stress associated with the activation of several signalling pathways, together with central insulin and leptin resistance. This central action of nutrient overload appears very rapidly, suggesting that nutrition-induced hypothalamic stress is a major upstream initiator of obesity and associated diseases. The cellular response to nutrient overload includes the activation of the stress-activated c-Jun N-terminal kinases (JNKs) JNK1, JNK2 and JNK3, which are widely expressed in the brain.

Opposing roles of JNK1 and JNK3 in the hypothalamus.

Here, we review recent findings on the regulation and effects of these kinases, with particular focus on the hypothalamus, a key brain region in the control of energy and glucose homeostasis. JNK1 blocks the hypothalamic–pituitary–thyroid axis, reducing energy expenditure and promoting obesity. Recently, opposing roles have been identified for JNK1 and JNK3 in hypothalamic agouti gene-related protein (AgRP) neurons: while JNK1 activation in AgRP neurons induces feeding and weight gain and impairs insulin and leptin signalling, JNK3 (also known as MAPK10) deletion in the same neuronal population produces very similar effects. The opposing roles of these kinases, and the unknown role of hypothalamic JNK2, reflect the complexity of JNK biology.

Future studies should address the specific function of each kinase, not only in different neuronal subsets, but also in non-neuronal cells in the central nervous system. Decoding the puzzle of brain stress kinases will help to define the central stimuli and mechanisms implicated in the control of energy balance.

Stress-activated kinases signaling pathways in cancer development

Leticia Herrera-Melle, María Crespo, Magdalena Leiva & Guadalupe Sabio.

Cancer is a large group of diseases characterized by abnormal cell growth that can lead to metastasis. It is the second leading cause of death worldwide, and its incidence is expected to rise over the next decades. Stress-activated protein kinases (SAPK) are important players in its regulation. Several studies have tried to unravel their role; however, their pro-tumorigenic or anti-tumorigenic properties are sometimes controversial.

JNK control of tumor microenvironment
JNK control of tumor microenvironment.

In this review, we will discuss the main roles of the different SAPK in the control of tumor development through essential processes such as cell proliferation, apoptosis or invasiveness. We will also show the latest discoveries regarding the contribution of SAPK in shaping tumor microenvironment through the regulation of organ crosstalk and immune cell response during cancer progression.

All these studies are relevant examples of how SAPK offer new therapeutic avenues for cancer patients that may help increase their survival.

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