Imidazole propionate is a driver and therapeutic target in atherosclerosis Annalaura Mastrangelo, Iñaki Robles-Vera, Diego Mañanes, Miguel Galán, Marcos Femenía-Muiña, Ana Redondo-Urzainqui, Rafael Barrero-Rodríguez, Eleftheria Papaioannou, Joaquín Amores-Iniesta, Ana Devesa, Manuel Lobo-González, Alba Carreras, Katharina R. Beck, Sophie Ivarsson, Anders Gummesson, Georgios Georgiopoulos, Manuel Rodrigo-Tapias, Sarai Martínez-Cano, Ivan Fernández-López, Vanessa Nuñez, Alessia Ferrarini, Naohiro Inohara, Kimon Stamatelopoulos, Alberto Benguría, Danay Cibrian, Francisco Sánchez-Madrid, Vanesa Alonso-Herranz, Ana Dopazo, Coral Barbas, Jesús Vázquez, Juan Antonio López, Alicia González-Martín, Gabriel Nuñez, Konstantinos Stellos, Göran Bergström, Fredrik Bäckhed, Valentín Fuster, Borja Ibañez, David Sancho Nature, 2025 Atherosclerosis is the main underlying cause of cardiovascular diseases. Its prevention is based on the detection and treatment of traditional cardiovascular risk factors1. However, individuals at risk for early vascular disease often remain unidentified2. Recent research has identified new molecules in the pathophysiology of atherosclerosis3, highlighting the need for alternative disease biomarkers and therapeutic targets to improve early diagnosis and therapy efficacy. Here, we observed that imidazole propionate (ImP), produced by microorganisms, is associated with the extent of atherosclerosis in mice and in two independent human cohorts. Furthermore, ImP administration to atherosclerosis-prone mice fed with chow diet was sufficient to induce atherosclerosis without altering the lipid profile, and was linked to activation of both systemic and local innate and adaptive immunity and inflammation. Specifically, we found that ImP caused atherosclerosis through the imidazoline-1 receptor (I1R, also known as nischarin) in myeloid cells. Blocking this ImP–I1R axis inhibited the development of atherosclerosis induced by ImP or high-cholesterol diet in mice. Identification of the strong association of ImP with active atherosclerosis and the contribution of the ImP–I1R axis to disease progression opens new avenues for improving the early diagnosis and personalized therapy of atherosclerosis. Imidazole propionate produced by gut microbiota is associated with atherosclerosis in mouse models and in humans, and causes the development of atherosclerosis through activation of the imidazoline-1 receptor in myeloid cells.
Restricting SLC7A5-mediated Leucine uptake in T cells prevents acute GVHD and maintains GVT response Nieves Fernández-Gallego, Blanca Anega, Susana Luengo-Arias, Maider Bizkarguenaga, Rubén Gil-Redondo, Nieves Embade, Laura Navarrete-Arias, Marta Ramírez-Huesca, Emigdio Álvarez-Corrales, Sara G Dosil, Raquel Castillo-González, Amelia Rojas-Gomez, Inés Espeleta, Sara Martínez-Martínez, Arantzazu Alfranca, Virginia G de Yebenes, Noa Beatriz Martín-Cófreces, Julián Aragonés, Pilar Martin, Oscar Millet, Francisco Sánchez-Madrid, Danay Cibrian EMBO Molecular Medicine, 2025 The L-Leu amino acid transporter SLC7A5 has become an important target in inflammation and cancer. However, its role in acute graft-versus-host disease (aGVHD) and graft versus tumor (GVT) remains unexplored. We demonstrate that SLC7A5 deletion affected T cell activation, expansion and survival, and reduced IFNγ and granzyme B expression, thus controlling aGVHD, but without effect on tumor growth. On the other hand, dietary restriction of L-Leu reduced aGVHD by controlling T cell expansion, inducing apoptosis, and affecting granzyme B secretion. However, CD8 T cells did not fail to activate and express IFNγ in the absence of L-Leu, and showed an increased proportion of central memory T cells, which contributed to the GVT response. Deletion of SLC7A5 in T cells compromises mTORC1, glycolysis and mitochondrial oxidation. On the contrary, L-Leu removal reduced mTORC1 and completely blocked glycolysis but preserved mitochondrial function, favoring the generation of central memory responses and expression of stemness marker TCF1. In addition, our metabolomics data underscores the L-Leu-derived metabolite β-hydroxybutyrate as an important marker for SLC7A5-dependent allogenic T cell expansion in aGVHD.
Growth hormone releasing peptide-6 (GHRP-6) prevents doxorubicin-induced myocardial and extra-myocardial damages by activating prosurvival mechanisms Jorge Berlanga-Acosta, Danay Cibrian, Juan Valiente-Mustelier, José Suárez-Alba, Ariana García-Ojalvo, Viviana Falcón-Cama, Baohong Jiang, Linlin Wang, Gerardo Guillén-Nieto Frontiers in Pharmacology, 2024 Introduction: Dilated cardiomyopathy (DCM) is a fatal myocardial condition with ventricular structural changes and functional deficits, leading to systolic dysfunction and heart failure (HF). DCM is a frequent complication in oncologic patients receiving Doxorubicin (Dox). Dox is a highly cardiotoxic drug, whereas its damaging spectrum affects most of the organs by multiple pathogenic cascades. Experimentally reproduced DCM/HF through Dox administrations has shed light on the pathogenic drivers of cardiotoxicity. Growth hormone (GH) releasing peptide 6 (GHRP-6) is a GH secretagogue with expanding and promising cardioprotective pharmacological properties. Here we examined whether GHRP-6 administration concomitant to Dox prevented the onset of DCM/HF and multiple organs damages in otherwise healthy rats.Methods: Myocardial changes were sequentially evaluated by transthoracic echocardiography. Autopsy was conducted at the end of the administration period when ventricular dilation was established. Semiquantitative histopathologic study included heart and other internal organs samples. Myocardial tissue fragments were also addressed for electron microscopy study, and characterization of the transcriptional expression ratio between Bcl-2 and Bax. Serum samples were destined for REDOX system balance assessment.Results and discussion: GHRP-6 administration in parallel to Dox prevented myocardial fibers consumption and ventricular dilation, accounting for an effective preservation of the LV systolic function. GHRP-6 also attenuated extracardiac toxicity preserving epithelial organs integrity, inhibiting interstitial fibrosis, and ultimately reducing morbidity and mortality. Mechanistically, GHRP-6 proved to sustain cellular antioxidant defense, upregulate prosurvival gene Bcl-2, and preserve cardiomyocyte mitochondrial integrity. These evidences contribute to pave potential avenues for the clinical use of GHRP-6 in Dox-treated subjects.
Erythroid SLC7A5/SLC3A2 amino acid carrier controls red blood cell size and maturation Antonio Bouthelier, Lucía Fernández-Arroyo, Claudia Mesa-Ciller, Danay Cibrian, Noa Beatriz Martín-Cófreces, Raquel Castillo-González, Macarena Calero, Diego Herráez-Aguilar, Andrea Guajardo-Grence, Ana María Pacheco, Ana Marcos-Jiménez, Borja Quiroga, Marta Morado, Francisco Monroy, Cecilia Muñoz-Calleja, Francisco Sánchez-Madrid, Andrés A. Urrutia, Julián Aragonés Iscience, 2023 -deficient reticulocytes are characterized by lower transferrin receptor (CD71) expression as well as mitochondrial activity, suggesting a premature transition to mature RBCs. These data reveal that SLC7A5/SLC3A2 ensures adequate maturation of reticulocytes as well as the proper size and hemoglobin content of circulating RBCs.
UNRAVELING CD69 SIGNALING PATHWAYS, LIGANDS AND LATERALLY ASSOCIATED MOLECULES Jiménez-Fernández, María, De La Fuente, Hortensia, Martín, Pilar, Cibrián, Danay, Sánchez-Madrid, Francisco Excli Journal, 2023 CD69 is an early leukocyte activation marker involved in the regulation of the immune response. Initial in vitro studies evaluated its function using monoclonal antibodies until knock-out mice were developed. Subsequently, four ligands for CD69 have been identified, namely galectin-1, S100A8/S100A9 complex, myosin light chains 9 and 12, and oxidized low-density lipoproteins. In addition, several molecules are laterally associated with and regulated by CD69, including calreticulin and two transmembrane receptors, sphingosine-1-phosphate receptor (S1P1) and the heterodimeric amino acid transporter complex SLC7A5-SLC3A2 (LAT1-CD98). Recently, CD69 engagement has been shown to induce the expression of the immunoregulatory receptor programmed cell death-1 (PD-1) in T cells. The molecular signaling induced by CD69 has been explored in different scenarios and cell types. This review provides a perspective on the molecular pathways, ligands and cellular functions known to be regulated by CD69.
Growth arrest and DNA damage-inducible proteins (GADD45) in psoriasis Pedro Rodríguez-Jiménez, Lola Fernández-Messina, María C. Ovejero-Benito, Pablo Chicharro, Paula Vera-Tomé, Alicia Vara, Danay Cibrian, Pedro Martínez-Fleta, María Jiménez-Fernández, Inés Sánchez-García, Mar Llamas-Velasco, Francisco Abad-Santos, Francisco Sánchez-Madrid, Esteban Dauden, Hortensia de la Fuente Scientific Reports, 2021 The interplay between T cells, dendritic cells and keratinocytes is crucial for the development and maintenance of inflammation in psoriasis. GADD45 proteins mediate DNA repair in different cells including keratinocytes. In the immune system, GADD45a and GADD45b regulate the function and activation of both T lymphocytes and dendritic cells and GADD45a links DNA repair and epigenetic regulation through its demethylase activity. Here, we analyzed the expression of GADD45a and GADD45b in the skin, dendritic cells and circulating T cells in a cohort of psoriasis patients and their regulation by inflammatory signals. Thirty patients (17 male/13 female) with plaque psoriasis and 15 controls subjects (7 male/8 female), were enrolled. Psoriasis patients exhibited a lower expression of GADD45a at the epidermis but a higher expression in dermal infiltrating T cells in lesional skin. The expression of GADD45a and GADD45b was also higher in peripheral T cells from psoriasis patients, although no differences were observed in p38 activation. The expression and methylation state of the GADD45a target UCHL1 were evaluated, revealing a hypermethylation of its promoter in lesional skin compared to controls. Furthermore, reduced levels of GADD45a correlated with a lower expression UCHL1 in lesional skin. We propose that the demethylase function of GADD45a may account for its pleiotropic effects, and the complex and heterogeneous pattern of expression observed in psoriatic disease.
Role of ahr ligands in skin homeostasis and cutaneous inflammation Nieves Fernández-Gallego, Francisco Sánchez-Madrid, Danay Cibrian Cells, 2021 Aryl hydrocarbon receptor (AHR) is an important regulator of skin barrier function. It also controls immune-mediated skin responses. The AHR modulates various physiological functions by acting as a sensor that mediates environment–cell interactions, particularly during immune and inflammatory responses. Diverse experimental systems have been used to assess the AHR’s role in skin inflammation, including in vitro assays of keratinocyte stimulation and murine models of psoriasis and atopic dermatitis. Similar approaches have addressed the role of AHR ligands, e.g., TCDD, FICZ, and microbiota-derived metabolites, in skin homeostasis and pathology. Tapinarof is a novel AHR-modulating agent that inhibits skin inflammation and enhances skin barrier function. The topical application of tapinarof is being evaluated in clinical trials to treat psoriasis and atopic dermatitis. In the present review, we summarize the effects of natural and synthetic AHR ligands in keratinocytes and inflammatory cells, and their relevance in normal skin homeostasis and cutaneous inflammatory diseases.
Expression of miR-135b in psoriatic skin and its association with disease improvement Pablo Chicharro, Pedro Rodríguez-Jiménez, Mar Llamas-Velasco, Nuria Montes, Ancor Sanz-García, Danay Cibrian, Alicia Vara, Manuel J Gómez, María Jiménez-Fernández, Pedro Martínez-Fleta, Inés Sánchez-García, Marta Lozano-Prieto, Juan C Triviño, Rebeca Miñambres, Francisco Sánchez-Madrid, Hortensia de la Fuente, Esteban Dauden Cells, 2020
CD13 as a new tumor target for antibody-drug conjugates: Validation with the conjugate MI130110 Juan Manuel Domínguez, Gema Pérez-Chacón, María José Guillén, María José Muñoz-Alonso, Beatriz Somovilla-Crespo, Danay Cibrián, Bárbara Acosta-Iborra, Magdalena Adrados, Cecilia Muñoz-Calleja, Carmen Cuevas, Francisco Sánchez-Madrid, Pablo Avilés, Juan M. Zapata Journal of Hematology and Oncology, 2020
Targeting L-type amino acid transporter 1 in innate and adaptive T cells efficiently controls skin inflammation Danay Cibrian, Raquel Castillo-González, Nieves Fernández-Gallego, Hortensia de la Fuente, Inmaculada Jorge, María Laura Saiz, Carmen Punzón, Marta Ramírez-Huesca, Miguel Vicente-Manzanares, Manuel Fresno, Esteban Daudén, Javier Fraga-Fernandez, Jesús Vazquez, Julián Aragonés, Francisco Sánchez-Madrid Journal of Allergy and Clinical Immunology, 2020
Thrombospondin-1/CD47 interaction regulates Th17 and treg differentiation in psoriasis Pedro Rodríguez-Jiménez, Pablo Chicharro, Mar Llamas-Velasco, Danay Cibrian, Laura Trigo-Torres, Alicia Vara, María Jiménez-Fernández, Javier Sevilla-Montero, Maria J. Calzada, Francisco Sánchez-Madrid, Hortensia de la Fuente, Esteban Daudén Frontiers in Immunology, 2019
First-in-class inhibitor of the T cell receptor for the treatment of autoimmune diseases Aldo Borroto, Diana Reyes-Garau, M. Angeles Jiménez, Esther Carrasco, Beatriz Moreno, Sara Martínez-Pasamar, José R. Cortés, Almudena Perona, David Abia, Soledad Blanco, Manuel Fuentes, Irene Arellano, Juan Lobo, Haleh Heidarieh, Javier Rueda, Pilar Esteve, Danay Cibrián, Ana Martinez-Riaño, Pilar Mendoza, Cristina Prieto, Enrique Calleja, Clara L. Oeste, Alberto Orfao, Manuel Fresno, Francisco Sánchez-Madrid, Antonio Alcamí, Paola Bovolenta, Pilar Martín, Pablo Villoslada, Antonio Morreale, Angel Messeguer, Balbino Alarcon Science Translational Medicine, 2016
