5 research outputs found
Peripheral blood mononuclear cells (PBMC) microbiome is not affected by colon microbiota in healthy goats
This work was supported by grants from the Spanish Ministry of Science and Innovation (MCI) co-financed with FEDER funds [AGL2017-86757 to LA, AGL2017-86938-R to DRY]. Other contributions were SAF2015-65327-R to JA and SAF2015-73549-JIN to HR. LA is a Ramón y Cajal fellow [RYC-2013-13666] from the Spanish Ministry of Science and Innovation. APC is a recipient of a fellowship from the University of the Basque Country. We thank the MCI for the Severo Ochoa Excellence accreditation (SEV-2016-0644) and the Basque Department of Industry, Tourism and Trade (Etortek and Elkartek programs
Microbioma de las células mononucleares de sangre periférica en cabras
1 página.- Trabajo presentado a las: XIX Jornadas sobre Producción Animal AIDA. On line. Zaragoza, España, 1-2 junio 2021.Financiado por los proyectos AGL2017-86757 y AGL2017-86938-R
Borrelia burgdorferi infection induces long-term memory-like responses in macrophages with tissue-wide consequences in the heart
Lyme carditis is an extracutaneous manifestation of Lyme disease characterized by episodes of atrioventricular block of varying degrees and additional, less reported cardiomyopathies. The molecular changes associated with the response to Borrelia burgdorferi over the course of infection are poorly understood. Here, we identify broad transcriptomic and proteomic changes in the heart during infection that reveal a profound down-regulation of mitochondrial components. We also describe the long-term functional modulation of macrophages exposed to live bacteria, characterized by an augmented glycolytic output, increased spirochetal binding and internalization, and reduced inflammatory responses. In vitro, glycolysis inhibition reduces the production of tumor necrosis factor (TNF) by memory macrophages, whereas in vivo, it produces the reversion of the memory phenotype, the recovery of tissue mitochondrial components, and decreased inflammation and spirochetal burdens. These results show that B. burgdorferi induces long-term, memory-like responses in macrophages with tissue-wide consequences that are amenable to be manipulated in vivo.Supported by grants from the Spanish Ministry of Science, Innovation and Universities (MCIU) co-financed with FEDER funds (SAF2015-65327-R and RTI2018-096494-B-100 to JA; BFU2016-76872-R to EB, AGL2017-86757-R to LA, SAF2017-87301-R to MLMC, SAF2015-64111-R to AP, SAF2015-73549-JIN to HR), Instituto de Salud Carlos III (PIE13/0004 to AP), the Basque Government Department of Health (2015111117 to LA), the Basque Foundation for Innovation and Health Research (BIOEF), through the EiTB Maratoia grant BIO15/CA/016/BS to MLMC, the regional Government of Andalusia co-funded by CEC and FEDER funds (Proyectos de Excelencia P12-CTS-2232) and Fundación Domingo Martínez (to AP). LA is supported by the Ramon y Cajal program (RYC-2013-13666). DB, MMR and TMM are recipients of MCIU FPI fellowships. ACG and AP are recipients of fellowships form the Basque Government. APC is a recipient of a fellowship from the University of the Basque Country. We thank the MCIU for the Severo Ochoa Excellence accreditation (SEV-2016-0644), the Basque Department of Industry, Tourism and Trade (Etortek and Elkartek programs), the Innovation Technology Department of the Bizkaia Province and the CIBERehd network. DB and JA are supported by a grant from the Jesús de Gangoiti Barrera Foundation
The outcome of boosting mitochondrial activity in alcohol-associated liver disease is organ-dependent.
BACKGROUND AND AIMS
Alcohol-associated liver disease (ALD) accounts for 70% of liver-related deaths in Europe, with no effective approved therapies. Although mitochondrial dysfunction is one of the earliest manifestations of alcohol-induced injury, restoring mitochondrial activity remains a problematic strategy due to oxidative stress. Here, we identify methylation-controlled J protein (MCJ) as a mediator for ALD progression and hypothesize that targeting MCJ may help in recovering mitochondrial fitness without collateral oxidative damage.
APPROACH AND RESULTS
C57BL/6 mice [wild-type (Wt)] Mcj knockout and Mcj liver-specific silencing (MCJ-LSS) underwent the NIAAA dietary protocol (Lieber-DeCarli diet containing 5% (vol/vol) ethanol for 10 days, plus a single binge ethanol feeding at day 11). To evaluate the impact of a restored mitochondrial activity in ALD, the liver, gut, and pancreas were characterized, focusing on lipid metabolism, glucose homeostasis, intestinal permeability, and microbiota composition. MCJ, a protein acting as an endogenous negative regulator of mitochondrial respiration, is downregulated in the early stages of ALD and increases with the severity of the disease. Whole-body deficiency of MCJ is detrimental during ALD because it exacerbates the systemic effects of alcohol abuse through altered intestinal permeability, increased endotoxemia, and dysregulation of pancreatic function, which overall worsens liver injury. On the other hand, liver-specific Mcj silencing prevents main ALD hallmarks, that is, mitochondrial dysfunction, steatosis, inflammation, and oxidative stress, as it restores the NAD + /NADH ratio and SIRT1 function, hence preventing de novo lipogenesis and improving lipid oxidation.
CONCLUSIONS
Improving mitochondrial respiration by liver-specific Mcj silencing might become a novel therapeutic approach for treating ALD.This work was supported by grants from Ministerio de
Ciencia e Innovación, Programa Retos-Colaboración
RTC2019-007125-1 (for Jorge Simon and Maria Luz
Martinez-Chantar); Ministerio de Economía, Industria y
Competitividad, Retos a la Sociedad AGL2017-
86927R (for F.M.); Instituto de Salud Carlos III,
Proyectos de Investigación en Salud DTS20/00138
and DTS21/00094 (for Jorge Simon and Maria Luz
Martinez-Chantar, and Asis Palazon. respectively);
Instituto de Salud Carlos III, Fondo de Investigaciones
Sanitarias co-founded by European Regional
Development Fund/European Social Fund, “Investing
in your future” PI19/00819, “Una manera de
hacer Europa” FIS PI20/00765, and PI21/01067 (for
Jose J. G. Marin., Pau Sancho-Bru,. and Mario F.
Fraga respectively); Departamento de Industria del
Gobierno Vasco (for Maria Luz Martinez-Chantar);
Asturias Government (PCTI) co-funding 2018-2023/
FEDER IDI/2021/000077 (for Mario F. Fraga.);
Ministerio de Ciencia, Innovación y Universidades
MICINN: PID2020-117116RB-I00, CEX2021-001136-S
PID2020-117941RB-I00, PID2020-11827RB-I00 and
PID2019-107956RA-100 integrado en el Plan Estatal
de Investigación Científica y Técnica y Innovación,
cofinanciado con Fondos FEDER (for Maria Luz Martinez-Chantar, Francisco J Cubero., Yulia A Nevzorova
and Asis Palazon); Ayudas Ramón y Cajal de la Agencia
Estatal de Investigación RY2013-13666 and RYC2018-
024183-I (for Leticia Abecia and Asis Palazon); European Research Council Starting Grant 804236 NEXTGEN-IO (for Asis Palazon); The German Research
Foundation SFB/TRR57/P04, SFB1382-403224013/
A02 and DFG NE 2128/2-1 (for Francisco J Cubero
and Yulia A Nevzorova); National Institute of Health (NIH)/National Institute of Alcohol Abuse and Alcoholism
(NIAAA) 1U01AA026972-01 (For Pau Sancho-Bru);
Junta de Castilla y León SA074P20 (for Jose J. G.
Marin); Junta de Andalucía, Grupo PAIDI BIO311 (for
Franz Martin); CIBERER Acciones Cooperativas y
Complementarias Intramurales ACCI20-35 (for Mario F.
Fraga); Ministerio de Educación, Cultura y Deporte
FPU17/04992 (for Silvia Ariño); Fundació Marato TV3
201916-31 (for Jose J. G. Marin.); Ainize Pena-Cearra is
a fellow of the University of the Basque Country (UPV/
EHU); BIOEF (Basque Foundation for Innovation and
Health Research); Asociación Española contra el Cáncer
(Maria Luz Martinez-Chantar and Teresa C. Delgado.);
Fundación Científica de la Asociación Española Contra
el Cáncer (AECC Scientific Foundation) Rare Tumor
Calls 2017 (for Maria Luz Martinez-Chantar); La Caixa
Foundation Program (for Maria Luz Martinez-Chantar);
Proyecto Desarrollo Tecnologico CIBERehd (for Maria
Luz Martinez-Chantar); Ciberehd_ISCIII_MINECO is
funded by the Instituto de Salud Carlos III.S
Bi-directional signaling between the intestinal epithelium and type-3 innate lymphoid cells regulates secretory dynamics and interleukin-22
Type-3 innate lymphoid cells (ILC3) respond to localized environmental cues to regulate homeostasis and orchestrate immunity in the intestine. The intestinal epithelium is an important upstream regulator and downstream target of ILC3 signaling, however, the complexity of mucosal tissues can hinder efforts to define specific interactions between these two compartments. Here, we employ a reductionist co-culture system of murine epithelial small intestinal organoids (SIO) with ILC3 to uncover bi-directional signaling mechanisms that underlie intestinal homeostasis. We report that ILC3 induce global transcriptional changes in intestinal epithelial cells, driving the enrichment of secretory goblet cell signatures. We find that SIO enriched for goblet cells promote NKp46+ ILC3 and interleukin (IL)-22 expression, which can feedback to induce IL-22-mediated epithelial transcriptional signatures. However, we show that epithelial regulation of ILC3 in this system is contact-dependent and demonstrate a role for epithelial Delta-Like-Canonical-Notch-Ligand (Dll) in driving IL-22 production by ILC3, via subset-specific Notch1-mediated activation of T-bet+ ILC3. Finally, by interfering with Notch ligand-receptor dynamics, ILC3 appear to upregulate epithelial Atoh1 to skew secretory lineage determination in SIO-ILC3 co-cultures. This research outlines two complimentary bi-directional signaling modules between the intestinal epithelium and ILC3, which may be relevant in intestinal homeostasis and disease.</p