Publications by authors named "Mercedes Ricote"

40 Publications

Nuclear receptors: Lipid and hormone sensors with essential roles in the control of cancer development.

Semin Cancer Biol 2020 Dec 9. Epub 2020 Dec 9.

Department of Cell Biology, Physiology and Immunology, School of Biology, University of Barcelona, Barcelona, 08028, Spain; Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, 08028, Spain. Electronic address:

Nuclear receptors (NRs) are a superfamily of ligand-activated transcription factors that act as biological sensors and use a combination of mechanisms to modulate positively and negatively gene expression in a spatial and temporal manner. The highly orchestrated biological actions of several NRs influence the proliferation, differentiation, and apoptosis of many different cell types. Synthetic ligands for several NRs have been the focus of extensive drug discovery efforts for cancer intervention. This review summarizes the roles in tumour growth and metastasis of several relevant NR family members, namely androgen receptor (AR), estrogen receptor (ER), glucocorticoid receptor (GR), thyroid hormone receptor (TR), retinoic acid receptors (RARs), retinoid X receptors (RXRs), peroxisome proliferator-activated receptors (PPARs), and liver X receptors (LXRs). These studies are key to develop improved therapeutic agents based on novel modes of action with reduced side effects and overcoming resistance.
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http://dx.doi.org/10.1016/j.semcancer.2020.12.007DOI Listing
December 2020

Endogenous and combination retinoids are active in myelomonocytic leukemias.

Haematologica 2021 04 1;106(4):1008-1021. Epub 2021 Apr 1.

Department of Internal Medicine, Washington University, St Louis, Missouri, 63110.

Retinoid therapy transformed response and survival outcomes in acute promyelocytic leukemia (APL), but has demonstrated only modest activity in non-APL forms of acute myeloid leukemia (AML). The presence of natural retinoids in vivo could influence the efficacy of pharmacologic agonists and antagonists. We found that natural RXRA ligands, but not RARA ligands, were present in murine MLL-AF9-derived myelomonocytic leukemias in vivo and that the concurrent presence of receptors and ligands acted as tumor suppressors. Pharmacologic retinoid responses could be optimized by concurrent targeting RXR ligands (e.g. bexarotene) and RARA ligands (e.g. all-trans retinoic acid, ATRA), which induced either leukemic maturation or apoptosis depending on cell culture conditions. Co-repressor release from the RARA:RXRA heterodimer occurred with RARA activation, but not RXRA activation, providing an explanation for the combination synergy. Combination synergy could be replicated in additional, but not all, AML cell lines and primary samples, and was associated with improved survival in vivo, although tolerability of bexarotene administration in mice remained an issue. These data provide insight into the basal presence of natural retinoids in leukemias in vivo and a potential strategy for clinical retinoid combination regimens in leukemias beyond acute promyelocytic leukemia.
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http://dx.doi.org/10.3324/haematol.2020.264432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017822PMC
April 2021

Macrophages promote endothelial-to-mesenchymal transition via MT1-MMP/TGFβ1 after myocardial infarction.

Elife 2020 10 16;9. Epub 2020 Oct 16.

Myocardial Pathophysiology Area, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.

Macrophages (Mφs) produce factors that participate in cardiac repair and remodeling after myocardial infarction (MI); however, how these factors crosstalk with other cell types mediating repair is not fully understood. Here we demonstrated that cardiac Mφs increased the expression of (MT1-MMP) 7 days post-MI. We selectively inactivated the gene in Mφs using a genetic strategy (:-Cre). This conditional KO (MAC-Mmp14 KO) resulted in attenuated post-MI cardiac dysfunction, reduced fibrosis, and preserved cardiac capillary network. Mechanistically, we showed that MT1-MMP activates latent TGFβ1 in Mφs, leading to paracrine SMAD2-mediated signaling in endothelial cells (ECs) and endothelial-to-mesenchymal transition (EndMT). Post-MI MAC-Mmp14 KO hearts contained fewer cells undergoing EndMT than their wild-type counterparts, and -deficient Mφs showed a reduced ability to induce EndMT in co-cultures with ECs. Our results indicate the contribution of EndMT to cardiac fibrosis and adverse remodeling post-MI and identify Mφ MT1-MMP as a key regulator of this process.
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http://dx.doi.org/10.7554/eLife.57920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609061PMC
October 2020

Molecular control of tissue-resident macrophage identity by nuclear receptors.

Curr Opin Pharmacol 2020 08 8;53:27-34. Epub 2020 May 8.

Area of Myocardial Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain. Electronic address:

Macrophages are key immune cells that reside in almost all tissues of the body, where they exert pleiotropic functions in homeostasis and disease. Development and identity of macrophages in each organ are governed by tissue-dependent signaling pathways and transcription factors that ultimately define specific tissue-resident macrophage phenotypes and functions. In recent years, nuclear receptors, a class of ligand-activated transcription factors, have been found to play important roles in macrophage specification in several tissues. Nuclear receptors are thus important targets for therapies aimed at controlling the numbers and functions of tissue-resident macrophages. This review outlines current knowledge about the critical roles of nuclear receptors in tissue-resident macrophage development, specification, and maintenance.
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http://dx.doi.org/10.1016/j.coph.2020.04.001DOI Listing
August 2020

RXRs control serous macrophage neonatal expansion and identity and contribute to ovarian cancer progression.

Nat Commun 2020 04 3;11(1):1655. Epub 2020 Apr 3.

Area of Myocardial Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.

Tissue-resident macrophages (TRMs) populate all tissues and play key roles in homeostasis, immunity and repair. TRMs express a molecular program that is mostly shaped by tissue cues. However, TRM identity and the mechanisms that maintain TRMs in tissues remain poorly understood. We recently found that serous-cavity TRMs (LPMs) are highly enriched in RXR transcripts and RXR-response elements. Here, we show that RXRs control mouse serous-macrophage identity by regulating chromatin accessibility and the transcriptional regulation of canonical macrophage genes. RXR deficiency impairs neonatal expansion of the LPM pool and reduces the survival of adult LPMs through excess lipid accumulation. We also find that peritoneal LPMs infiltrate early ovarian tumours and that RXR deletion diminishes LPM accumulation in tumours and strongly reduces ovarian tumour progression in mice. Our study reveals that RXR signalling controls the maintenance of the serous macrophage pool and that targeting peritoneal LPMs may improve ovarian cancer outcomes.
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http://dx.doi.org/10.1038/s41467-020-15371-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7125161PMC
April 2020

Brain Cleanup as a Potential Target for Poststroke Recovery: The Role of RXR (Retinoic X Receptor) in Phagocytes.

Stroke 2020 03 9;51(3):958-966. Epub 2020 Jan 9.

From the Department of Neurology, University of Texas HSC, McGovern Medical School, Houston (S.-M.T., X.Z., G.S., L.O., J.A.).

Background and Purpose- Phagocytic cells, such as microglia and blood-derived macrophages, are a key biological modality responsible for phagocytosis-mediated clearance of damaged, dead, or displaced cells that are compromised during senescence or pathological processes, including after stroke. This process of clearance is essential to eliminate the source of inflammation and to allow for optimal brain repair and functional recovery. Transcription factor, RXR (retinoic-X-receptor) is strongly implicated in phagocytic functions regulation, and as such could represent a novel target for brain recovery after stroke. Methods- Primary cultured microglia and bone marrow macrophages were used for phagocytic study. Mice with deleted RXR-α in myeloid phagocytes (Mac-RXR-α) were subjected to transient middle cerebral artery occlusion to mimic ischemic stroke and then treated with RXR agonist bexarotene. RNA-sequencing and long-term recovery were evaluated. Results- Using cultured microglia, we demonstrated that the RXR-α promotes the phagocytic functions of microglia toward apoptotic neurons. Using mice with deleted RXR-α in myeloid phagocytes (Mac-RXR-α), we have shown that despite behaving similarly to the control at early time points (up to 3 days, damage established histologically and behaviorally), these Mac-RXR-α mice demonstrated worsened late functional recovery and developed brain atrophy that was larger in size than that seen in control mice. The RXR-α deficiency was associated with reduced expression of genes known to be under control of the prominent transcriptional RXR partner, PPAR (peroxisome proliferator-activated receptor)-γ, as well as genes encoding for scavenger receptors and genes that signify microglia/macrophages polarization to a reparative phenotype. Finally, we demonstrated that the RXR agonist, bexarotene, administered as late as 1 day after middle cerebral artery occlusion, improved neurological recovery, and reduced the atrophy volume as assessed 28 days after stroke. Bexarotene did not improve outcome in Mac-RXR-α mice. Conclusions- Altogether, these data suggest that phagocytic cells control poststroke recovery and that RXR in these cells represents an attractive target with exceptionally long therapeutic window.
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http://dx.doi.org/10.1161/STROKEAHA.119.027315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042051PMC
March 2020

Spanish primary care survey on the management of Helicobacter pylori infection and dyspepsia: Information, attitudes, and decisions.

Helicobacter 2019 Aug 20;24(4):e12593. Epub 2019 May 20.

Gastroenterology Unit, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Universidad Autónoma de Madrid (UAM) and Asociación Española de Gastroenterología (AEG), Madrid, Spain.

Introduction: Dyspepsia and Helicobacter pylori are two of the most relevant digestive conditions in primary care. Several consensuses on the subject have been published, but the assimilation/implementation of these guidelines is uncertain.

Aims And Methods: To evaluate the attitudes, perceptions, limitations, and adherence to recommendations of Spanish primary care physicians using an open online survey. Responses were anonymously codified. Estimated margin of error was 3.4%. Responses were weighted by province, gender, age, and type of practice. Survey was performed using the AEG-REDCap platform.

Results: A total of 1445 responses, received between December 2017 and April 2018, were analyzed. Women represented 54%, and the average age was 48 years; 59% were from urban context, 20% from semi-urban, and 21% from rural; 93% provided public practice. Over 40% had read at least one Maastricht consensus (24% Maastricht V), and 34% had attended a course related to H. pylori. 16% reported no direct access to any validated diagnostic method, only 44% to urea breath test, and 33% did not systematically refer to eradication confirmation test. The first-line treatment of choice was standard triple therapy in 56%, followed by concomitant therapy (28%). Only 20% of physicians had optimal adherence to recommendations.

Conclusion: Even though some improvements from guidelines have been partially incorporated, the level of penetration of recommendations is still poor and delayed. To provide optimal primary care, the barriers for implementation, access to diagnostic tests and to continuous medical education, should be removed. Rigorous dissemination, implementation, and evaluation programs are desired in future consensuses.
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http://dx.doi.org/10.1111/hel.12593DOI Listing
August 2019

Isolation and Purification of Tissue Resident Macrophages for the Analysis of Nuclear Receptor Activity.

Methods Mol Biol 2019 ;1951:59-73

Myocardial Pathophysiology Area, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.

Tissue resident macrophages (TRMs) are multifunctional immune cells present in all tissues, contributing to the correct development, homeostasis, and protection against pathogens and injury. TRMs are morphologically and functionally heterogeneous, as a result of both the diversity of tissue environments in which they reside and their complex origin. Furthermore, some specific TRM populations are controlled by nuclear receptors. A widely used method for studying the role of nuclear receptors in immune cells is flow cytometry. Although flow cytometry is extensively used in tissues such as the peripheral blood, lymph nodes, peritoneal cavity, and bone marrow, there is a need for protocols for the study TRMs in solid tissues.In this chapter, we describe a comprehensive protocol for obtaining single-cell suspensions of resident macrophages from the pleural cavity, heart, lung, spleen, and kidney, and we present detailed gating strategies for the study of nuclear receptor activity in different TRM subsets within these tissues.
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http://dx.doi.org/10.1007/978-1-4939-9130-3_5DOI Listing
July 2019

Flow Cytometry Has a Significant Impact on the Cellular Metabolome.

J Proteome Res 2019 01 2;18(1):169-181. Epub 2018 Nov 2.

Centro de Metabolómica y Bioanálisis (CEMBIO), Facultad de Farmacia , Universidad CEU San Pablo , Campus Montepríncipe , Madrid 28668 , Spain.

The characterization of specialized cell subpopulations in a heterogeneous tissue is essential for understanding organ function in health and disease. A popular method of cell isolation is fluorescence-activated cell sorting (FACS) based on probes that bind surface or intracellular markers. In this study, we analyze the impact of FACS on the cell metabolome of mouse peritoneal macrophages. Compared with directly pelleted macrophages, FACS-treated cells had an altered content of metabolites related to the plasma membrane, activating a mechanosensory signaling cascade causing inflammation-like stress. The procedure also triggered alterations related to energy consumption and cell damage. The observed changes mostly derive from the physical impact on cells during their passage through the instrument. These findings provide evidence of FACS-induced biochemical changes, which should be taken into account in the design of robust metabolic assays of cells separated by flow cytometry.
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http://dx.doi.org/10.1021/acs.jproteome.8b00472DOI Listing
January 2019

Deciphering the Dynamic Transcriptional and Post-transcriptional Networks of Macrophages in the Healthy Heart and after Myocardial Injury.

Cell Rep 2018 Apr;23(2):622-636

Myocardial Pathophysiology Area, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), 28029 Madrid, Spain. Electronic address:

Macrophage plasticity has been studied in vitro, but transcriptional regulation upon injury is poorly understood. We generated a valuable dataset that captures transcriptional changes in the healthy heart and after myocardial injury, revealing a dynamic transcriptional landscape of macrophage activation. Partial deconvolution suggested that post-injury macrophages exhibit overlapping activation of pro-inflammatory and anti-inflammatory programs rather than aligning to canonical M1/M2 programs. Furthermore, simulated dynamics and experimental validation of a regulatory core of the underlying gene-regulatory network revealed a negative-feedback loop that limits initial inflammation via hypoxia-mediated upregulation of Il10. Our results also highlight the prominence of post-transcriptional regulation (miRNAs, mRNA decay, and lincRNAs) in attenuating the myocardial injury-induced inflammatory response. We also identified a cardiac-macrophage-specific gene signature (e.g., Egfr and Lifr) and time-specific markers for macrophage populations (e.g., Lyve1, Cd40, and Mrc1). Altogether, these data provide a core resource for deciphering the transcriptional network in cardiac macrophages in vivo.
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http://dx.doi.org/10.1016/j.celrep.2018.03.029DOI Listing
April 2018

MT4-MMP deficiency increases patrolling monocyte recruitment to early lesions and accelerates atherosclerosis.

Nat Commun 2018 03 2;9(1):910. Epub 2018 Mar 2.

Matrix Metalloproteinases in Angiogenesis and Inflammation Group, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Melchor Fernández Almagro 3, 28029, Madrid, Spain.

Matrix metalloproteinases are involved in vascular remodeling. Little is known about their immune regulatory role in atherosclerosis. Here we show that mice deficient for MT4-MMP have increased adherence of macrophages to inflamed peritonea, and larger lipid deposits and macrophage burden in atherosclerotic plaques. We also demonstrate that MT4-MMP deficiency results in higher numbers of patrolling monocytes crawling and adhered to inflamed endothelia, and the accumulation of Mafb+ apoptosis inhibitor of macrophage (AIM)+ macrophages at incipient atherosclerotic lesions in mice. Functionally, MT4-MMP-null Mafb+AIM+ peritoneal macrophages express higher AIM and scavenger receptor CD36, are more resistant to apoptosis, and bind acLDL avidly, all of which contribute to atherosclerosis. CCR5 inhibition alleviates these effects by hindering the enhanced recruitment of MT4-MMP-null patrolling monocytes to early atherosclerotic lesions, thus blocking Mafb+AIM+ macrophage accumulation and atherosclerosis acceleration. Our results suggest that MT4-MMP targeting may constitute a novel strategy to boost patrolling monocyte activity in early inflammation.
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http://dx.doi.org/10.1038/s41467-018-03351-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834547PMC
March 2018

Infarct Fibroblasts Do Not Derive From Bone Marrow Lineages.

Circ Res 2018 02 21;122(4):583-590. Epub 2017 Dec 21.

From the Aix Marseille Univ, INSERM, UMR_S910, GMGF, France (T.M.-M., M.P.); Skaggs School of Pharmacy and Pharmaceutical Sciences (P.C., N.G.-C., L.Z., S.M.E.), Department of Medicine (J.B., Y.G., N.D.D., K.L.P., J.C., S.M.E.), and Department of Pharmacology (I.B., S.M.E.), University of California at San Diego, La Jolla; National Research Council, Institute of Genetics and Biomedical Research, Milan Unit, Italy (P.C.); Humanitas Clinical and Research Center, Rozzano (MI), Italy (P.C.); and Cardiovascular Development and Repair Department, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (M.C., M.R.).

Rationale: Myocardial infarction is a major cause of adult mortality worldwide. The origin(s) of cardiac fibroblasts that constitute the postinfarct scar remain controversial, in particular the potential contribution of bone marrow lineages to activated fibroblasts within the scar.

Objective: The aim of this study was to establish the origin(s) of infarct fibroblasts using lineage tracing and bone marrow transplants and a robust marker for cardiac fibroblasts, the Collagen1a1-green fluorescent protein reporter.

Methods And Results: Using genetic lineage tracing or bone marrow transplant, we found no evidence for collagen-producing fibroblasts derived from hematopoietic or bone marrow lineages in hearts subjected to permanent left anterior descending coronary artery ligation. In fact, fibroblasts within the infarcted area were largely of epicardial origin. Intriguingly, collagen-producing fibrocytes from hematopoietic lineages were observed attached to the epicardial surface of infarcted and sham-operated hearts in which a suture was placed around the left anterior descending coronary artery.

Conclusions: In this controversial field, our study demonstrated that the vast majority of infarct fibroblasts were of epicardial origin and not derived from bone marrow lineages, endothelial-to-mesenchymal transition, or blood. We also noted the presence of collagen-producing fibrocytes on the epicardial surface that resulted at least in part from the surgical procedure.
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http://dx.doi.org/10.1161/CIRCRESAHA.117.311490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5815911PMC
February 2018

Endogenous retinoid X receptor ligands in mouse hematopoietic cells.

Sci Signal 2017 Oct 31;10(503). Epub 2017 Oct 31.

Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.

The retinoid X receptor α (RXRA) has been implicated in diverse hematological processes. To identify natural ligands of RXRA that are present in hematopoietic cells, we adapted an upstream activation sequence-green fluorescent protein (UAS-GFP) reporter mouse to detect natural RXRA ligands in vivo. We observed reporter activity in diverse types of hematopoietic cells in vivo. Reporter activity increased during granulocyte colony-stimulating factor (G-CSF)-induced granulopoiesis and after phenylhydrazine (PHZ)-induced anemia, suggesting the presence of dynamically regulated natural RXRA ligands in hematopoietic cells. Mouse plasma activated Gal4-UAS reporter cells in vitro, and plasma from mice treated with G-CSF or PHZ recapitulated the patterns of reporter activation that we observed in vivo. Plasma from mice with dietary vitamin A deficiency only mildly reduced RXRA reporter activity, whereas plasma from mice on a fatty acid restriction diet reduced reporter activity, implicating fatty acids as plasma RXRA ligands. Through differential extraction coupled with mass spectrometry, we identified the long-chain fatty acid C24:5 as a natural RXRA ligand that was greatly increased in abundance in response to hematopoietic stress. Together, these data suggest that natural RXRA ligands are present and dynamically increased in abundance in mouse hematopoietic cells in vivo.
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http://dx.doi.org/10.1126/scisignal.aan1011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5777239PMC
October 2017

Phagocytosis imprints heterogeneity in tissue-resident macrophages.

J Exp Med 2017 05 21;214(5):1281-1296. Epub 2017 Apr 21.

Area of Cell and Developmental Biology, Centro Nacional de Investigaciones Cardiovasculares Carlos III, 28029 Madrid, Spain.

Tissue-resident macrophages display varying phenotypic and functional properties that are largely specified by their local environment. One of these functions, phagocytosis, mediates the natural disposal of billions of cells, but its mechanisms and consequences within living tissues are poorly defined. Using a parabiosis-based strategy, we identified and isolated macrophages from multiple tissues as they phagocytosed blood-borne cellular material. Phagocytosis was circadianally regulated and mediated by distinct repertoires of receptors, opsonins, and transcription factors in macrophages from each tissue. Although the tissue of residence defined the core signature of macrophages, phagocytosis imprinted a distinct antiinflammatory profile. Phagocytic macrophages expressed CD206, displayed blunted expression of , and supported tissue homeostasis. Thus, phagocytosis is a source of macrophage heterogeneity that acts together with tissue-derived factors to preserve homeostasis.
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http://dx.doi.org/10.1084/jem.20161375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5413334PMC
May 2017

The multi-faceted role of retinoid X receptor in bone remodeling.

Cell Mol Life Sci 2017 06 19;74(12):2135-2149. Epub 2017 Jan 19.

Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Melchor Fernández Almagro, 3, 28029, Madrid, Spain.

Retinoid X receptors (RXRs) form a unique subclass within the nuclear receptor (NR) superfamily of ligand-dependent transcription factors. RXRs are obligatory partners for a number of other NRs, placing RXRs in a coordinating role at the crossroads of multiple signaling pathways. In addition, RXRs can function as self-sufficient homodimers. Recent advances have revealed RXRs as novel regulators of osteoclastogenesis and bone remodeling. This review outlines the versatility of RXR action in the control of transcription of bone-forming osteoblasts and bone-resorbing osteoclasts, both through heterodimerization with other NRs and through RXR homodimerization. RXR signaling is currently a major therapeutic target and, therefore, knowledge of how RXR signaling affects bone remodeling creates enormous potential for the translation of basic research findings into successful clinical therapies to increase bone mass and improve bone quality.
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http://dx.doi.org/10.1007/s00018-017-2458-4DOI Listing
June 2017

Peroxisome proliferator activated receptor gamma 2 modulates late pregnancy homeostatic metabolic adaptations.

Mol Med 2016 Dec 19;22:724-736. Epub 2016 Oct 19.

University Rey Juan Carlos, Department of Basic Sciences of Health, Area of Biochemistry and Molecular Biology, Avda. de Atenas s/n, Alcorcon, 28922 Madrid, Spain.

Pregnancy requires the adaptation of maternal energy metabolism including expansion and functional modifications of adipose tissue. Insulin resistance (IR), predominantly during late gestation, is a physiological metabolic adaptation that serves to support the metabolic demands of fetal growth. The molecular mechanisms underlying these adaptations are not fully understood and may contribute to gestational diabetes mellitus. Peroxisome proliferator-activated receptor gamma (PPARγ) controls adipogenesis, glucose and lipid metabolism and insulin sensitivity. The PPARγ2 isoform is mainly expressed in adipocytes and is thus likely to contribute to adipose tissue adaptation during late pregnancy. In the present study, we investigated the contribution of PPARγ2 to the metabolic adaptations occurring during the late phase of pregnancy in the context of IR. Using a model of late pregnancy in PPARγ2 knockout (KO) mice, we found that deletion of PPARγ2 exacerbated IR in association with lower serum adiponectin levels, increased body weight and enhanced lipid accumulation in liver. Lack of PPARγ2 provoked changes in the distribution of fat mass and preferentially prevented the expansion of the perigonadal depot while at the same time exacerbating inflammation. PPARγ2KO pregnant mice presented adipose tissue depot-dependent decreased expression of genes involved in lipid metabolism. Collectively, these data indicate that PPARγ2 is essential to promote healthy adipose tissue expansion and immune and metabolic functionality during pregnancy, contributing to the physiological adaptations that lead gestation to term.
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http://dx.doi.org/10.2119/molmed.2015.00262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5135083PMC
December 2016

Retinoid X receptor activation reverses age-related deficiencies in myelin debris phagocytosis and remyelination.

Brain 2015 Dec 12;138(Pt 12):3581-97. Epub 2015 Oct 12.

1 Wellcome Trust-MRC Cambridge Stem Cell Institute, and Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0AH, UK

The efficiency of central nervous system remyelination declines with age. This is in part due to an age-associated decline in the phagocytic removal of myelin debris, which contains inhibitors of oligodendrocyte progenitor cell differentiation. In this study, we show that expression of genes involved in the retinoid X receptor pathway are decreased with ageing in both myelin-phagocytosing human monocytes and mouse macrophages using a combination of in vivo and in vitro approaches. Disruption of retinoid X receptor function in young macrophages, using the antagonist HX531, mimics ageing by reducing myelin debris uptake. Macrophage-specific RXRα (Rxra) knockout mice revealed that loss of function in young mice caused delayed myelin debris uptake and slowed remyelination after experimentally-induced demyelination. Alternatively, retinoid X receptor agonists partially restored myelin debris phagocytosis in aged macrophages. The agonist bexarotene, when used in concentrations achievable in human subjects, caused a reversion of the gene expression profile in multiple sclerosis patient monocytes to a more youthful profile and enhanced myelin debris phagocytosis by patient cells. These results reveal the retinoid X receptor pathway as a positive regulator of myelin debris clearance and a key player in the age-related decline in remyelination that may be targeted by available or newly-developed therapeutics.
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http://dx.doi.org/10.1093/brain/awv289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4668920PMC
December 2015

GOplot: an R package for visually combining expression data with functional analysis.

Bioinformatics 2015 Sep 11;31(17):2912-4. Epub 2015 May 11.

Department of Cardiovascular Development and Repair and.

Unlabelled: Despite the plethora of methods available for the functional analysis of omics data, obtaining comprehensive-yet detailed understanding of the results remains challenging. This is mainly due to the lack of publicly available tools for the visualization of this type of information. Here we present an R package called GOplot, based on ggplot2, for enhanced graphical representation. Our package takes the output of any general enrichment analysis and generates plots at different levels of detail: from a general overview to identify the most enriched categories (bar plot, bubble plot) to a more detailed view displaying different types of information for molecules in a given set of categories (circle plot, chord plot, cluster plot). The package provides a deeper insight into omics data and allows scientists to generate insightful plots with only a few lines of code to easily communicate the findings.

Availability And Implementation: The R package GOplot is available via CRAN-The Comprehensive R Archive Network: http://cran.r-project.org/web/packages/GOplot. The shiny web application of the Venn diagram can be found at: https://wwalter.shinyapps.io/Venn/. A detailed manual of the package with sample figures can be found at https://wencke.github.io/

Contact: fscabo@cnic.es or mricote@cnic.es.
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http://dx.doi.org/10.1093/bioinformatics/btv300DOI Listing
September 2015

Retinoid X receptors orchestrate osteoclast differentiation and postnatal bone remodeling.

J Clin Invest 2015 Feb 9;125(2):809-23. Epub 2015 Jan 9.

Osteoclasts are bone-resorbing cells that are important for maintenance of bone remodeling and mineral homeostasis. Regulation of osteoclast differentiation and activity is important for the pathogenesis and treatment of diseases associated with bone loss. Here, we demonstrate that retinoid X receptors (RXRs) are key elements of the transcriptional program of differentiating osteoclasts. Loss of RXR function in hematopoietic cells resulted in formation of giant, nonresorbing osteoclasts and increased bone mass in male mice and protected female mice from bone loss following ovariectomy, which induces osteoporosis in WT females. The increase in bone mass associated with RXR deficiency was due to lack of expression of the RXR-dependent transcription factor v-maf musculoaponeurotic fibrosarcoma oncogene family, protein B (MAFB) in osteoclast progenitors. Evaluation of osteoclast progenitor cells revealed that RXR homodimers directly target and bind to the Mafb promoter, and this interaction is required for proper osteoclast proliferation, differentiation, and activity. Pharmacological activation of RXRs inhibited osteoclast differentiation due to the formation of RXR/liver X receptor (LXR) heterodimers, which induced expression of sterol regulatory element binding protein-1c (SREBP-1c), resulting in indirect MAFB upregulation. Our study reveals that RXR signaling mediates bone homeostasis and suggests that RXRs have potential as targets for the treatment of bone pathologies such as osteoporosis.
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http://dx.doi.org/10.1172/JCI77186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4319420PMC
February 2015

Retinoid X receptor α attenuates host antiviral response by suppressing type I interferon.

Nat Commun 2014 Nov 24;5:5494. Epub 2014 Nov 24.

Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, California 90095, USA.

The retinoid X receptor α (RXRα), a key nuclear receptor in metabolic processes, is downregulated during host antiviral response. However, the roles of RXRα in host antiviral response are unknown. Here we show that RXRα overexpression or ligand activation increases host susceptibility to viral infections in vitro and in vivo, while Rxra-/- or antagonist treatment reduces infection by the same viruses. Consistent with these functional studies, ligand activation of RXR inhibits the expression of antiviral genes including type I interferon (IFN) and Rxra-/- macrophages produce more IFNβ than WT macrophages in response to polyI:C stimulation. Further results indicate that ligand activation of RXR suppresses the nuclear translocation of β-catenin, a co-activator of IFNβ enhanceosome. Thus, our studies have uncovered a novel RXR-dependent innate immune regulatory pathway, suggesting that the downregulation of RXR expression or RXR antagonist treatment benefits host antiviral response, whereas RXR agonist treatment may increase the risk of viral infections.
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http://dx.doi.org/10.1038/ncomms6494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4380327PMC
November 2014

Rosiglitazone-induced CD36 up-regulation resolves inflammation by PPARγ and 5-LO-dependent pathways.

J Leukoc Biol 2014 Apr 12;95(4):587-98. Epub 2013 Dec 12.

2.Depto. de Farmacología, Facultad de Medicina, Universidad Complutense, Avda. Complutense s/n, 28040 Madrid, Spain.

PPARγ-achieved neuroprotection in experimental stroke has been explained by the inhibition of inflammatory genes, an action in which 5-LO, Alox5, is involved. In addition, PPARγ is known to promote the expression of CD36, a scavenger receptor that binds lipoproteins and mediates bacterial recognition and also phagocytosis. As phagocytic clearance of neutrophils is a requisite for resolution of the inflammatory response, PPARγ-induced CD36 expression might help to limit inflammatory tissue injury in stroke, an effect in which 5-LO might also be involved. Homogenates, sections, and cellular suspensions were prepared from brains of WT and Alox5(-/-) mice exposed to distal pMCAO. BMMs were obtained from Lys-M Cre(+) PPARγ(f/f) and Lys-M Cre(-) PPARγ(f/f) mice. Stereological counting of double-immunofluorescence-labeled brain sections and FACS analysis of cell suspensions was performed. In vivo and in vitro phagocytosis of neutrophils by microglia/macrophages was analyzed. PPARγ activation with RSG induced CD36 expression in resident microglia. This process was mediated by the 5-LO gene, which is induced in neurons by PPARγ activation and at least by one of its products--LXA4--which induced CD36 independently of PPARγ. Moreover, CD36 expression helped resolution of inflammation through phagocytosis, concomitantly to neuroprotection. Based on these findings, in addition to a direct modulation by PPARγ, we propose in brain a paracrine model by which products generated by neuronal 5-LO, such as LXA4, increase the microglial expression of CD36 and promote tissue repair in pathologies with an inflammatory component, such as stroke.
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http://dx.doi.org/10.1189/jlb.0613326DOI Listing
April 2014

Retinoid X receptors in macrophage biology.

Trends Endocrinol Metab 2013 Sep 20;24(9):460-8. Epub 2013 May 20.

Cardiovascular Development and Repair Department, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Melchor Fernández Almagro 3, 28029 Madrid, Spain.

Retinoid X receptors (RXRs) form a distinct and unique subclass within the nuclear receptor (NR) superfamily of ligand-dependent transcription factors. RXRs regulate a plethora of genetic programs, including cell differentiation, the immune response, and lipid and glucose metabolism. Recent advances reveal that RXRs are important regulators of macrophages, key players in inflammatory and metabolic disorders. This review outlines the versatility of RXR action in the control of macrophage gene transcription through its heterodimerization with other NRs or through RXR homodimerization. We also highlight the potential of RXR-controlled transcriptional programs as targets for the treatment of pathologies associated with altered macrophage function, such as atherosclerosis, insulin resistance, autoimmunity, and neurodegeneration.
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http://dx.doi.org/10.1016/j.tem.2013.04.004DOI Listing
September 2013

Biology and therapeutic applications of peroxisome proliferator- activated receptors.

Curr Top Med Chem 2012 ;12(6):548-84

Cardiovascular Development and Repair Department, Centro Nacional de Investigaciones Cardiovasculares-CNIC, Melchor Fernández Almagro 3, 28029 Madrid, Spain.

Peroxisome proliferator-activated receptors (PPARs) are ligand dependent transcription factors. The three mammalian PPARs are key regulators of fatty acid and lipoprotein metabolism, glucose homeostasis, cellular proliferation/ differentiation and the immune response. PPARs are therefore important targets in the treatment of metabolic disorders such as insulin resistance and type 2 diabetes mellitus, and are also of interest in relation to chronic inflammatory diseases such as atherosclerosis, arthritis, chronic pulmonary inflammation, pancreatitis, inflammatory bowel disease, and psoriasis. Recent advances have attributed novel functions to PPARs in blood pressure regulation, neuroinflammation, nerve-cell protection, inflammatory pain reduction, and the hypothalamic control of metabolism. The abundant pleiotropic actions of PPARs suggest that PPAR agonists have enormous therapeutic potential. However, current PPAR-based therapies often have undesired side effects due to the concomitant activation of PPARs in non-target cells. There is therefore growing interest in the development of cell-specific PPAR agonists and improvement of the clinical use of PPAR ligands. This review gives an overview of PPAR functions and discusses the current and potential medical implications of PPAR ligands in various pathologies, ranging from metabolic disorders to cardiovascular disease, chronic inflammation, neurodegenerative disorders and cancer.
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http://dx.doi.org/10.2174/156802612799436669DOI Listing
September 2012

Differential lipid partitioning between adipocytes and tissue macrophages modulates macrophage lipotoxicity and M2/M1 polarization in obese mice.

Diabetes 2011 Mar 24;60(3):797-809. Epub 2011 Jan 24.

Institute of Metabolic Science, Metabolic Research Laboratories, and Department of Clinical Biochemistry, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.

Objective: Obesity-associated insulin resistance is characterized by a state of chronic, low-grade inflammation that is associated with the accumulation of M1 proinflammatory macrophages in adipose tissue. Although different evidence explains the mechanisms linking the expansion of adipose tissue and adipose tissue macrophage (ATM) polarization, in the current study we investigated the concept of lipid-induced toxicity as the pathogenic link that could explain the trigger of this response.

Research Design And Methods: We addressed this question using isolated ATMs and adipocytes from genetic and diet-induced murine models of obesity. Through transcriptomic and lipidomic analysis, we created a model integrating transcript and lipid species networks simultaneously occurring in adipocytes and ATMs and their reversibility by thiazolidinedione treatment.

Results: We show that polarization of ATMs is associated with lipid accumulation and the consequent formation of foam cell-like cells in adipose tissue. Our study reveals that early stages of adipose tissue expansion are characterized by M2-polarized ATMs and that progressive lipid accumulation within ATMs heralds the M1 polarization, a macrophage phenotype associated with severe obesity and insulin resistance. Furthermore, rosiglitazone treatment, which promotes redistribution of lipids toward adipocytes and extends the M2 ATM polarization state, prevents the lipid alterations associated with M1 ATM polarization.

Conclusions: Our data indicate that the M1 ATM polarization in obesity might be a macrophage-specific manifestation of a more general lipotoxic pathogenic mechanism. This indicates that strategies to optimize fat deposition and repartitioning toward adipocytes might improve insulin sensitivity by preventing ATM lipotoxicity and M1 polarization.
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http://dx.doi.org/10.2337/db10-0705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3046840PMC
March 2011

Autoimmune kidney disease and impaired engulfment of apoptotic cells in mice with macrophage peroxisome proliferator-activated receptor gamma or retinoid X receptor alpha deficiency.

J Immunol 2011 Jan 6;186(1):621-31. Epub 2010 Dec 6.

Departamento de Cardiología Regenerativa, Centro Nacional de Investigaciones Cardiovasculares, 28029 Madrid, Spain.

Autoimmune glomerulonephritis is a common manifestation of systemic lupus erythematosus (SLE). In this study, we show that mice lacking macrophage expression of the heterodimeric nuclear receptors PPARγ or RXRα develop glomerulonephritis and autoantibodies to nuclear Ags, resembling the nephritis seen in SLE. These mice show deficiencies in phagocytosis and clearance of apoptotic cells, and they are unable to acquire an anti-inflammatory phenotype upon feeding of apoptotic cells, which is critical for the maintenance of self-tolerance. These results demonstrate that stimulation of PPARγ and RXRα in macrophages facilitates apoptotic cell engulfment, and they provide a potential strategy to avoid autoimmunity against dying cells and to attenuate SLE.
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http://dx.doi.org/10.4049/jimmunol.1002230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4038038PMC
January 2011

PPARs in the Renal Regulation of Systemic Blood Pressure.

PPAR Res 2010 8;2010:698730. Epub 2010 Jun 8.

Department of Regenerative Cardiology, Spanish National Cardiovascular Research Center (CNIC), 28029 Madrid, Spain.

Recent research has revealed roles for the peroxisome proliferator activated receptor (PPAR) family of transcription factors in blood pressure regulation, expanding the possible therapeutic use of PPAR ligands. PPARalpha and PPARgamma modulate the renin-angiotensin-aldosterone system (RAAS), a major regulator of systemic blood pressure and interstitial fluid volume by transcriptional control of renin, angiotensinogen, angiotensin converting enzyme (ACE) and angiotensin II receptor 1 (AT-R1). Blockade of RAAS is an important therapeutic target in hypertension management and attenuates microvascular damage, glomerular inflammation and left ventricular hypertrophy in hypertensive patients and also show antidiabetic effects. The mechanisms underlying the benefits of RAAS inhibition appear to involve PPARgamma-regulated pathways. This review summarizes current knowledge on the role of PPARs in the transcriptional control of the RAAS and the possible use of PPAR ligands in the treatment of RAAS dependent hypertension.
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http://dx.doi.org/10.1155/2010/698730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2896854PMC
July 2011

Inflammatory mediators and insulin resistance in obesity: role of nuclear receptor signaling in macrophages.

Mediators Inflamm 2010 20;2010:219583. Epub 2010 May 20.

Department of Regenerative Cardiology, Centro Nacional de Investigaciones Cardiovasculares, Instituto de Salud Carlos III, 28029 Madrid, Spain.

Visceral obesity is coupled to a general low-grade chronic inflammatory state characterized by macrophage activation and inflammatory cytokine production, leading to insulin resistance (IR). The balance between proinflammatory M1 and antiinflammatory M2 macrophage phenotypes within visceral adipose tissue appears to be crucially involved in the development of obesity-associated IR and consequent metabolic abnormalities. The ligand-dependent transcription factors peroxisome proliferator activated receptors (PPARs) have recently been implicated in the determination of the M1/M2 phenotype. Liver X receptors (LXRs), which form another subgroup of the nuclear receptor superfamily, are also important regulators of proinflammatory cytokine production in macrophages. Disregulation of macrophage-mediated inflammation by PPARs and LXRs therefore underlies the development of IR. This review summarizes the role of PPAR and LXR signaling in macrophages and current knowledge about the impact of these actions in the manifestation of IR and obesity comorbidities such as liver steatosis and diabetic osteopenia.
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http://dx.doi.org/10.1155/2010/219583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2874923PMC
September 2010

Retinoid X receptor alpha controls innate inflammatory responses through the up-regulation of chemokine expression.

Proc Natl Acad Sci U S A 2010 Jun 24;107(23):10626-31. Epub 2010 May 24.

Department of Regenerative Cardiology, Centro Nacional de Investigaciones Cardiovasculares, Madrid 28029, Spain.

The retinoid X receptor alpha (RXRalpha) plays a central role in the regulation of many intracellular receptor signaling pathways and can mediate ligand-dependent transcription by forming homodimers or heterodimers with other nuclear receptors. Although several members of the nuclear hormone receptor superfamily have emerged as important regulators of macrophage gene expression, the existence in vivo of an RXR signaling pathway in macrophages has not been established. Here, we provide evidence that RXRalpha regulates the transcription of the chemokines Ccl6 and Ccl9 in macrophages independently of heterodimeric partners. Mice lacking RXRalpha in myeloid cells exhibit reduced levels of CCL6 and CCL9, impaired recruitment of leukocytes to sites of inflammation, and lower susceptibility to sepsis. These studies demonstrate that macrophage RXRalpha plays key roles in the regulation of innate immunity and represents a potential target for immunotherapy of sepsis.
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http://dx.doi.org/10.1073/pnas.0913545107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2890831PMC
June 2010

Lipotoxicity in macrophages: evidence from diseases associated with the metabolic syndrome.

Biochim Biophys Acta 2010 Mar 29;1801(3):327-37. Epub 2009 Sep 29.

Institute of Metabolic Science, Metabolic Research Laboratories and Department of Clinical Biochemistry, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.

Accumulation of lipid metabolites within non-adipose tissues can induce chronic inflammation by promoting macrophage infiltration and activation. Oxidized and glycated lipoproteins, free fatty acids, free cholesterol, triacylglycerols, diacylglycerols and ceramides have long been known to induce cellular dysfunction through their pro-inflammatory and pro-apoptotic properties. Emerging evidence suggests that macrophage activation by lipid metabolites and further modulation by lipid signaling represents a common pathogenic mechanism underlying lipotoxicity in atherosclerosis, obesity-associated insulin resistance and inflammatory diseases related to metabolic syndrome such as liver steatosis and chronic kidney disease. In this review, we discuss the latest discoveries that support the role of lipids in modulating the macrophage phenotype in different metabolic diseases. We describe the common mechanisms by which lipid derivatives, through modulation of macrophage function, promote plaque instability in the arterial wall, impair insulin responsiveness and contribute to inflammatory liver, muscle and kidney disease. We discuss the molecular mechanism of lipid activation of pro-inflammatory pathways (JNK, NFkappaB) and the key roles played by the PPAR and LXR nuclear receptors-lipid sensors that link lipid metabolism and inflammation.
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http://dx.doi.org/10.1016/j.bbalip.2009.09.017DOI Listing
March 2010

Macrophage peroxisome proliferator activated receptor gamma as a therapeutic target to combat Type 2 diabetes.

Expert Opin Ther Targets 2007 Nov;11(11):1503-20

University of California, Department of Cellular Molecular Medicine, La Jolla, San Diego, California 92093, USA.

The peroxisome proliferator activated receptor gamma is a member of the nuclear receptor superfamily of ligand-dependent transcription factors and is the molecular target of antidiabetic thiazolidinediones that exert insulin sensitizing effects in adipose tissue, skeletal muscle and the liver. In addition to the well described effects of peroxisome proliferator activated receptor gamma in insulin target tissues, it is now apparent that its expression in macrophages is critical in the regulation of macrophage phenotype, whole body glucose metabolism and in mediating, in part, the antidiabetic actions of thiazolidinediones. As macrophages are major contributors to tissue inflammation and are resident in tissues responsible for maintaining glucose homeostasis, the therapeutic potential of these cells in the treatment of Type 2 diabetes is of significant clinical interest.
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http://dx.doi.org/10.1517/14728222.11.11.1503DOI Listing
November 2007