Category: Publications (Page 19 of 19)

p38? and p38? reprogram liver metabolism by modulating neutrophil infiltration

03/02/2016 / Sabio lab

Bárbara González?Terán, Nuria Matesanz, Ivana Nikolic, María Angeles Verdugo, Vinatha Sreeramkumar, Lourdes Hernández?Cosido, Alfonso Mora, Georgiana Crainiciuc, María Laura Sáiz, Edgar Bernardo, Luis Leiva?Vega, Elena Rodríguez, Victor Bondía, Jorge L Torres, Sonia Perez?Sieira, Luis Ortega, Ana Cuenda, Francisco Sanchez?Madrid, Rubén Nogueiras, Andrés Hidalgo, Miguel Marcos & Guadalupe Sabio.

Non?alcoholic fatty liver disease (NAFLD) is a major health problem and the main cause of liver disease in Western countries. Although NAFLD is strongly associated with obesity and insulin resistance, its pathogenesis remains poorly understood.

The disease begins with an excessive accumulation of triglycerides in the liver, which stimulates an inflammatory response. Alternative p38 mitogen?activated kinases (p38? and p38?) have been shown to contribute to inflammation in different diseases. Here we demonstrate that p38? is elevated in livers of obese patients with NAFLD and that mice lacking p38?/? in myeloid cells are resistant to diet?induced fatty liver, hepatic triglyceride accumulation and glucose intolerance. This protective effect is due to defective migration of p38?/??deficient neutrophils to the damaged liver.

We further show that neutrophil infiltration in wild?type mice contributes to steatosis development by means of inflammation and liver metabolic changes. Therefore, p38? and p38? in myeloid cells provide a potential target for NAFLD therapy.

EMBO J. 2016; 35(5): 536-552.

p38? and ? promote heart hypertrophy by targeting the mTOR-inhibitory protein DEPTOR for degradation

10/01/2016 / Sabio lab

Bárbara González-Terán, Juan Antonio López, Elena Rodríguez, Luis Leiva, Sara Martínez-Martínez, Juan Antonio Bernal, Luis Jesús Jiménez-Borreguero, Juan Miguel Redondo, Jesús Vazquez & Guadalupe Sabio.

heart

Disrupted organ growth leads to disease development. Hypertrophy underlies postnatal heart growth and is triggered after stress, but the molecular mechanisms involved in these processes are largely unknown.

Here we show that cardiac activation of p38? and p38? increases during postnatal development and by hypertrophy-inducing stimuli. p38?/? promote cardiac hypertrophy by phosphorylating the mTORC1 and mTORC2 inhibitor DEPTOR, which leads to its degradation and mTOR activation. Hearts from mice lacking one or both kinases are below normal size, have high levels of DEPTOR, low activity of the mTOR pathway and reduced protein synthesis. The phenotype of p38?/?^?/? mice is reverted by overactivation of mTOR with amino acids, shRNA-mediated knockdown of Deptor, or cardiomyocyte overexpression of active p38? and p38?. Moreover, in WT mice, heart weight is reduced by cardiac overexpression of DEPTOR.

Our results demonstrate that p38?/? control heart growth by modulating mTOR pathway through DEPTOR phosphorylation and subsequent degradation.

Nature Communications 7, doi: 10.1038/ncomms10477

Specific calcineurin targeting in macrophages confers resistance to inflammation via MKP-1 and p38

03/03/2014 / Sabio lab

Amelia Escolano, Sara Martínez?Martínez, Arántzazu Alfranca, Katia Urso, Helena M Izquierdo, Mario Delgado, Francisco Martín, Guadalupe Sabio, David Sancho, Pablo Gómez?del Arco & Juan Miguel Redondo.

Macrophages contribute to tissue homeostasis and influence inflammatory responses by modulating their phenotype in response to the local environment. Understanding the molecular mechanisms governing this plasticity would open new avenues for the treatment for inflammatory disorders.

p38 phosphorylation in macrophages.

We show that deletion of calcineurin (CN) or its inhibition with LxVP peptide in macrophages induces an anti-inflammatory population that confers resistance to arthritis and contact hypersensitivity. Transfer of CN-targeted macrophages or direct injection of LxVP-encoding lentivirus has anti-inflammatory effects in these models. Specific CN targeting in macrophages induces p38 MAPK activity by downregulating MKP-1 expression. However, pharmacological CN inhibition with cyclosporin A (CsA) or FK506 did not reproduce these effects and failed to induce p38 activity. The CN-inhibitory peptide VIVIT also failed to reproduce the effects of LxVP. p38 inhibition prevented the anti-inflammatory phenotype of CN-targeted macrophages, and mice with defective p38-activation were resistant to the anti-inflammatory effect of LxVP.

Our results identify a key role for CN and p38 in the modulation of macrophage phenotype and suggest an alternative treatment for inflammation based on redirecting macrophages toward an anti-inflammatory status.

EMBO J. 2014; 33(10): 1117-1133.