Sabio lab

at the CNIO

Tag: inflammation (Page 1 of 3)

Lack of p38 activation in T cells increases IL-35 and protects against obesity by promoting thermogenesis

10/05/2024 /

Ivana Nikolić, Irene Ruiz-Garrido, María Crespo, Rafael Romero-Becerra, Luis Leiva-Vega, Alfonso Mora, Marta León, Elena Rodríguez, Magdalena Leiva, Ana Belén Plata-Gómez, Maria Beatriz Alvarez Flores, Jorge L Torres, Lourdes Hernández-Cosido, Juan Antonio López, Jesús Vázquez, Alejo Efeyan, Pilar Martin, Miguel Marcos & Guadalupe Sabio.

Obesity is characterized by low-grade inflammation, energy imbalance and impaired thermogenesis. The role of regulatory T cells (Treg) in inflammation-mediated maladaptive thermogenesis is not well established.

Reduction of fat mass of mice lacking MKK3/6 as seen by MRI (Image: Ivana Nikolić).

Here, we find that the p38 pathway is a key regulator of T cell-mediated adipose tissue (AT) inflammation and browning. Mice with T cells specifically lacking the p38 activators MKK3/6 are protected against diet-induced obesity, leading to an improved metabolic profile, increased browning, and enhanced thermogenesis. We identify IL-35 as a driver of adipocyte thermogenic program through the ATF2/UCP1/FGF21 pathway. IL-35 limits CD8+ T cell infiltration and inflammation in AT. Interestingly, we find that IL-35 levels are reduced in visceral fat from obese patients.

Mechanistically, we demonstrate that p38 controls the expression of IL-35 in human and mouse Treg cells through mTOR pathway activation. Our findings highlight p38 signaling as a molecular orchestrator of AT T cell accumulation and function.

EMBO Rep 2024; 25: 2635-2661.

Predominantly pro-inflammatory phenotype with mixed M1/M2 polarization of peripheral blood classical monocytes and monocyte-derived macrophages among patients with excessive ethanol intake

07/09/2023 /

María Fernández-Regueras, Cristina Carbonell, Daniel Salete-Granado, Juan-Luis García, Marcos Gragera, María-Ángeles Pérez-Nieto, Francisco-Javier Morán-Plata, Andrea Mayado, Jorge-Luis Torres, Luis-Antonio Corchete, Ricardo Usategui-Martín, Elena Bueno-Martínez, Maura Rojas-Pirela, Guadalupe Sabio, Rogelio González-Sarmiento, Alberto Orfao, Francisco-Javier Laso, Julia Almeida & Miguel Marcos.

Excessive alcohol consumption impairs the immune system, induces oxidative stress, and triggers the activation of peripheral blood (PB) monocytes, thereby contributing to alcoholic liver disease (ALD).

miRNA of isolated CD14+ blood monocytes from excessive alcohol drinkers.

We analyzed the M1/M2 phenotypes of circulating classical monocytes and macrophage-derived monocytes (MDMs) in excessive alcohol drinkers (EADs). PB samples from 20 EADs and 22 healthy controls were collected for isolation of CD14+ monocytes and short-term culture with LPS/IFNγ, IL4/IL13, or without stimulation. These conditions were also used to polarize MDMs into M1, M2, or M0 phenotypes. Cytokine production was assessed in the blood and culture supernatants. M1/M2-related markers were analyzed using mRNA expression and surface marker detection. Additionally, the miRNA profile of CD14+ monocytes was analyzed. PB samples from EADs exhibited increased levels of pro-inflammatory cytokines. Following short-term culture, unstimulated blood samples from EADs showed higher levels of soluble TNF-α and IL-8, whereas monocytes expressed increased levels of surface TNF-α and elevated mRNA expression of pro-inflammatory cytokines and inducible nitric oxide synthase. MDMs from EADs showed higher levels of TNF-α and CD206 surface markers and increased IL-10 production. LPS/IFNγ induced higher mRNA expression of Nrf2 only in the controls. miRNA analysis revealed a distinctive miRNA profile that is potentially associated with liver carcinogenesis and ALD through inflammation and oxidative stress.

This study confirms the predominantly pro-inflammatory profile of PB monocytes among EADs and suggests immune exhaustion features in MDMs.

Antioxidants. 2023; 12 (9): 1708.

Hepatic stellate cell activation markers are regulated by the vagus nerve in systemic inflammation

31/03/2023 /

Osman Ahmed, April S. Caravaca, María Crespo, Wanmin Dai, Ting Liu, Qi Guo , Magdalena Leiva, Guadalupe Sabio, Vladimir S. Shavva, Stephen G. Malin & Peder S. Olofsson.

The liver is an important immunological organ and liver inflammation is part of the pathophysiology of non-alcoholic steatohepatitis, a condition that may promote cirrhosis, liver cancer, liver failure, and cardiovascular disease. Despite dense innervation of the liver parenchyma, little is known about neural regulation of liver function in inflammation. Here, we study vagus nerve control of the liver response to acute inflammation.

Detection by FACS of activated hepatic stellate cells (Image: María Crespo).

Methods: Male C57BL/6 J mice were subjected to either sham surgery, surgical vagotomy, or electrical vagus nerve stimulation followed by intraperitoneal injection of the TLR2 agonist zymosan. Animals were euthanized and tissues collected 12 h after injection. Samples were analyzed by qPCR, RNAseq, flow cytometry, or ELISA.

Results: Hepatic mRNA levels of pro-inflammatory mediators Ccl2, Il-1β, and Tnf-α were significantly higher in vagotomized mice compared with mice subjected to sham surgery. Differences in liver Ccl2 levels between treatment groups were largely reflected in the plasma chemokine (C-C motif) ligand 2 (CCL2) concentration. In line with this, we observed a higher number of macrophages in the livers of vagotomized mice compared with sham as measured by flow cytometry. In mice subjected to electrical vagus nerve stimulation, hepatic mRNA levels of Ccl2, Il1β, and Tnf-α, and plasma CCL2 levels, were significantly lower compared with sham. Interestingly, RNAseq revealed that a key activation marker for hepatic stellate cells (HSC), Pnpla3, was the most significantly differentially expressed gene between vagotomized and sham mice. Of note, several HSC-activation associated transcripts were higher in vagotomized mice, suggesting that signals in the vagus nerve contribute to HSC activation. In support of this, we observed significantly higher number of activated HSCs in vagotomized mice as compared with sham as measured by flow cytometry.

Conclusions: Signals in the cervical vagus nerve controlled hepatic inflammation and markers of HSC activation in zymosan-induced peritonitis.

Bioelectron Med. 2023; 9 (1): 6.

« Older posts

Findacio La Caixa

Fundación Princesa de Girona

Asociación Española Contra el Cáncer

Fundación BBVA

European Foundation for the Study of Diabetes

© 2024 Sabio lab

Theme by Anders Norén — Up ↑