Person:
Angelina Querencias, Alba

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First Name
Alba
Last Name
Angelina Querencias
Affiliation
Universidad Complutense de Madrid
Faculty / Institute
Ciencias Químicas
Department
Bioquímica y Biología Molecular
Area
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Search Results

Now showing 1 - 10 of 13
  • Publication
    The cannabinoid WIN55212-2 restores rhinovirus-induced epithelial barrier disruption
    (John Wiley & Sons, 2020-12-15) Angelina Querencias, Alba; Martín Fontecha, María del Mar; Rückert, Beate; Wawrzyniak, Paulina; Pérez Diego, Mario; López Abente, Jacobo; Akdis, Mübeccel; Akdis, Cezmi A.; Palomares, Oscar
  • Publication
    Cannabinoid WIN55212-2 impairs peanut-allergic sensitization and promotes the generation of allergen-specific regulatory T cells
    (Wiley, 2022-01-07) Angelina Querencias, Alba; Jiménez Saiz, Rodrigo; Pérez Diego, Mario; Maldonado, Ángel; Rückert, Beate; Akdis, Mübeccel; Martín Fontecha, María del Mar; Akdis, Cezmi A.; Palomares, Oscar
    Background: Cannabinoids are lipid-derived mediators with anti-inflammatory prop-erties in different diseases. WIN55212-2, a non-selective synthetic cannabinoid, re-duces immediate anaphylactic reactions in a mouse model of peanut allergy, but its capacity to prevent peanut-allergic sensitization and the underlying mechanisms re-mains largely unknown. Objective: To investigate the capacity of WIN55212-2 to immunomodulate peanut- stimulated human dendritic cells (DCs) and peanut-allergic sensitization in mice. Methods: Surface markers and cytokines were quantified by flow cytometry, ELISA and qPCR in human monocyte-derived DCs (hmoDCs) and T-cell cocultures after stimulation with peanut alone or in the presence of WIN55212-2. Mice were epicuta-neously sensitized with peanut alone or peanut/WIN55212-2. After peanut challenge, drop in body temperature, haematocrit, clinical symptoms, peanut-specific antibodies in serum and FOXP3+ regulatory (Treg) cells in spleen and lymph nodes were quanti-fied. Splenocytes were stimulated in vitro with peanut to analyse allergen-specific T- cell responses. Results: WIN55212-2 reduced peanut-induced hmoDC activation and promoted the generation of CD4+CD127−CD25+FOXP3+ Treg cells, while reducing the induction of IL- 5- producing T cells. In vivo, WIN55212-2 impaired the peanut-induced migration of DCs to lymph nodes and their maturation. WIN55212-2 significantly reduced the induction of peanut-specific IgE and IgG1 antibodies in serum during epicutaneous peanut sensitization, reduced the clinical symptoms score upon peanut challenge and promoted the generation of allergen-specific FOXP3+ Treg cells. Conclusions: The synthetic cannabinoid WIN55212-2 interferes with peanut sensi-tization and promotes tolerogenic responses, which might well pave the way for the development of novel prophylactic and therapeutic strategies for peanut allergy.
  • Publication
    The cannabinoid WIN55212-2 suppresses effector T-cell responses and promotes regulatory T cells in human tonsils
    (John Wiley & Sons, 2021-10-28) Angelina Querencias, Alba; Pérez Diego, Mario; Maldonado, Ángel; Rückert, Beate; Akdis, Mübeccel; Martín Fontecha, María del Mar; Akdis, Cezmi A.; Palomares, Oscar
  • Publication
    Allergoid–mannan conjugates reprogram monocytes into tolerogenic dendritic cells via epigenetic and metabolic rewiring
    (Elsevier, 2022-06-18) Benito Villalvilla, Cristina; Pérez Diego, Mario; Angelina Querencias, Alba; Kisand, Kai; Rebane, Ana; Subiza, José Luis; Palomares Gracia, Oscar
    Allergoid–mannan conjugates are novel vaccines for allergen-specific immunotherapy being currently assayed in phase 2 clinical trials. Allergoid–mannan conjugates target dendritic cells (DCs) and generate functional forkhead box P3 (FOXP3)-positive Treg cells, but their capacity to reprogram monocyte differentiation remains unknown.
  • Publication
    Cannabinoids and immunomodulation: novel therapeutic strategies targeting dendritic cells for inflammatory diseases
    (Universidad Complutense de Madrid, 2021-06-08) Angelina Querencias, Alba; Palomares Gracia, Óscar
    Dendritic cells (DCs) are professional antigen presenting cells that play a key role in the orchestration of immune responses by linking innate and adaptive immunity. The main function of DCs is to capture antigens in the periphery and transport them to the closer lymph nodes. There, they present the processed antigens to naïve T cells, inducing T cell activation and polarization into different phenotypes depending on the antigen, the environmental cues, costimulatory signals and cytokines. Changes in the energetic metabolism of DCs are essential for the regulation of their functional properties. At this regard, several studies have reported the involvement of autophagy, an essential catabolic process, in the control of DC functions. The endocannabinoid system (ECS) is a complex signalling network involved in many physiological processes such as neuronal development, brain plasticity, memory, cell survival, metabolism and immunity. The main components of the ECS include the endocannabinoid ligands, the cannabinoid receptors (CBRs) and the enzymes related to the ligand synthesis or degradation. Several studies showed that cannabinoid compounds display anti-inflammatory properties in different immune-mediated diseases. However, their potential capacity to regulate the orchestration of immune responses is not well understood, specifically in humans. Human DCs express all the components of the ECS. The ability of cannabinoids to immunomodulate the phenotype and function of DCs remain elusive. Considering all these aspects, the main objective of this Doctoral Thesis is to investigate the role and the underlying molecular mechanisms of synthetic cannabinoids in the control of human DC function and their potential implications in preclinical in vitro and in vivo models of immune-mediated diseases as potential novel strategies for the prevention and treatment of inflammatory disorders. In this work, we have developed and validated a novel HU210-Alexa488 fluorescence probe to visualize and quantify CB1-expressing cells in peripheral blood and tonsils by flow cytometry and confocal microscopy. We have also demonstrated for the first time that the synthetic cannabinoid WIN55212-2 promotes the generation of tolerogenic DCs with the capacity to generate functional FOXP3+ regulatory T (Treg) cells by mechanisms depending on CB1- and PPARα-mediated autophagy induction. We have validated the potential relevance of our findings in different preclinical human and mouse models. The synthetic cannabinoid WIN55212-2 exhibits in vivo protective and anti-inflammatory effects in LPS-induced sepsis model by mechanisms that rely on autophagy induction via activation of CB1 and PPARα. In a mouse model of peanut food allergy, the administration of WIN55212-2 during peanut challenge protects peanut-allergic mice from the immediate anaphylactic reaction. Moreover, WIN55212-2 administration promotes the generation of allergen-specific FOXP3+ regulatory T cells during late-phase responses. Finally, we have demonstrated that WIN55212-2 repairs rhinovirus-induced airway epithelial disruption by restoring the integrity of tight junction proteins without affecting epithelial cell-mediated innate immune response. In summary, in this Doctoral Thesis we uncover the previously unknown capacity of the synthetic cannabinoid WIN55212-2 to immunomodulate the phenotype and function of human DCs. We show for the first time the molecular mechanisms by which WIN55212-2 imprints tolerogenic features in human DCs, which include CB1- and PPARα-mediated autophagy induction and metabolic reprogramming. In addition, we have demonstrated the potential clinical applications of WIN55212-2 in different in vitro and in vivo preclinical human and mouse models such as sepsis, peanut allergy or rhinovirus-induced inflammation. The data presented in this Doctoral Thesis might well contribute to pave the way for the future development of novel cannabinoid-based strategies for the prevention and treatment of immune-mediated diseases.
  • Publication
    Cannabinoids induce functional Tregs by promoting tolerogenic DCs via autophagy and metabolic reprograming
    (Springer Nature, 2021-09-21) Angelina Querencias, Alba; Pérez Diego, Mario; López Abente, Jacobo; Rückert, Beate; Nombela, Iván; Akdis, Mübeccel; Martín Fontecha, María del Mar; Akdis, Cezmi A.; Palomares, Oscar
    The generation of functional regulatory T cells (Tregs) is essential to keep tissue homeostasis and restore healthy immune responses in many biological and inflammatory contexts. Cannabinoids have been pointed out as potential therapeutic tools for several diseases. Dendritic cells (DCs) express the endocannabinoid system, including the cannabinoid receptors CB1 and CB2. However, how cannabinoids might regulate functional properties of DCs is not completely understood. We uncover that the triggering of cannabinoid receptors promote human tolerogenic DCs that are able to prime functional FOXP3+ Tregs in the context of different inflammatory diseases. Mechanistically, cannabinoids imprint tolerogenicity in human DCs by inhibiting NF-κB, MAPK and mTOR signalling pathways while inducing AMPK and functional autophagy flux via CB1- and PPARα-mediated activation, which drives metabolic rewiring towards increased mitochondrial activity and oxidative phosphorylation. Cannabinoids exhibit in vivo protective and anti-inflammatory effects in LPS-induced sepsis and also promote the generation of FOXP3+ Tregs. In addition, immediate anaphylactic reactions are decreased in peanut allergic mice and the generation of allergen-specific FOXP3+ Tregs are promoted, demonstrating that these immunomodulatory effects take place in both type 1- and type 2-mediated inflammatory diseases. Our findings might open new avenues for novel cannabinoid-based interventions in different inflammatory and immune-mediated diseases.
  • Publication
    A tumor-associated heparan sulfate-related glycosaminoglycan promotes the generation of functional regulatory T cells
    (CHIN SOCIETY IMMUNOLOGY, 2023-11-22) Leticia Martín-Cruz; Marcos Viñuela; Ioanna Kalograiaki; Alba Angelina; Paola Oquist-Phillips; Irene Real-Arévalo; Francisco Javier Cañada; José Ignacio Tudela; Luis Moltó; Jesús Moreno-Sierra; José Luis Subiza; Oscar Palomares; Moreno Sierra, Jesús; Martín De La Cruz, Leticia; Angelina Querencias, Alba; Palomares Gracia, Óscar
    Functional Tregs play a key role in tumor development and progression, representing a major barrier to anticancer immunity. The mechanisms by which Tregs are generated in cancer and the influence of the tumor microenvironment on these processes remain incompletely understood. Herein, by using NMR, chemoenzymatic structural assays and a plethora of in vitro and in vivo functional analyses, we demonstrate that the tumoral carbohydrate A10 (Ca10), a cell-surface carbohydrate derived from Ehrlich’s tumor (ET) cells, is a heparan sulfate-related proteoglycan that enhances glycolysis and promotes the development of tolerogenic features in human DCs. Ca10-stimulated human DCs generate highly suppressive Tregs by mechanisms partially dependent on metabolic reprogramming, PD-L1, IL-10, and IDO. Ca10 also reprograms the differentiation of human monocytes into DCs with tolerogenic features. In solid ET-bearing mice, we found positive correlations between Ca10 serum levels, tumor size and splenic Treg numbers. Administration of isolated Ca10 also increases the proportion of splenic Tregs in tumor-free mice. Remarkably, we provide evidence supporting the presence of a circulating human Ca10 counterpart (Ca10H) and show, for the first time, that serum levels of Ca10H are increased in patients suffering from different cancer types compared to healthy individuals. Of note, these levels are higher in prostate cancer patients with bone metastases than in prostate cancer patients without metastases. Collectively, we reveal novel molecular mechanisms by which heparan sulfate-related structures associated with tumor cells promote the generation of functional Tregs in cancer. The discovery of this novel structural-functional relationship may open new avenues of research with important clinical implications in cancer treatment.
  • Publication
    From trained immunity in allergy to trained immunity‐based allergen vaccines.
    (2022-12-09) Sevilla Ortega, Carmen; Angelina Querencias, Alba; Domínguez Andrés, Jorge; Netea, Mihai G.; Subiza, José Luis; Palomares, Oscar; Martín De La Cruz, Leticia
    Innate immune cells experience long lasting metabolic and epigenetic changes after an encounter with specific stimuli. This facilitates enhanced immune responses upon secondary exposition to both the same and unrelated pathogens, a process termed trained immunity. Trained immunity- based vaccines (TIbV) are vaccines able to induce innate immune memory, thus conferring heterologous protection against a broad range of pathogens. While trained immunity has been well documented in the con-text of infections and multiple immune- mediated diseases, the role of innate immune memory and its contribution to the initiation and maintenance of chronic allergic dis-eases remains poorly understood. Over the last years, different studies attempting to uncover the role of trained immunity in allergy have emerged. Exposition to en-vironmental factors impacting allergy development such as allergens or viruses in-duces the reprogramming of innate immune cells to acquire a more pro-inflammatory phenotype in the context of asthma or food allergy. Several studies have convincingly demonstrated that prevention of viral infections using TIbV contributes to reduce wheezing attacks in children, which represent a high- risk factor for asthma develop-ment later in life. Innate immune cells trained with specific stimuli might also acquire anti- inflammatory features and promote tolerance, which may have important impli-cations for chronic inflammatory diseases such as allergies. Recent findings showed that allergoid- mannan conjugates, which are next generation vaccines for allergen- specific immunotherapy (AIT), are able to reprogram monocytes into tolerogenic den-dritic cells by mechanisms depending on metabolic and epigenetic rewiring. A better understanding of the underlying mechanisms of trained immunity in allergy will pave the way for the design of novel trained immunity- based allergen vaccines as potential alternative strategies for the prevention and treatment of allergic diseases.
  • Publication
    Development of a Fluorescent Bodipy Probe for Visualization of the Serotonin 5-HT1A Receptor in Native Cells of the Immune System
    (American Chemical Society (ACS), 2018-05-07) Hernández Torres, Gloria; Enríquez Palacios, Ernesto; Mecha Rodríguez, Miriam; Feliú Martínez, Ana; Rueda Zubiaurre, Ainoa; Angelina Querencias, Alba; Martín Fontecha, María del Mar; Palomares, Oscar; Guaza Rodríguez, Carmen; Peña Cabrera, Eduardo; López Rodríguez, María L.; Ortega Gutiérrez, Silvia; Martín De La Cruz, Leticia
    Serotonin (5-HT) modulates key aspects of the immune system. However, its precise function and the receptors involved in the observed effects have remained elusive. Among the different serotonin receptors, 5-HT1A plays an important role in the immune system given its presence in cells involved in both the innate and adaptive immune responses, but its actual levels of expression under different conditions have not been comprehensively studied due to the lack of suitable tools. To further clarify the role of 5-HT1A receptor in the immune system, we have developed a fluorescent small molecule probe that enables the direct study of the receptor levels in native cells. This probe allows direct profiling of the receptor expression in immune cells using flow cytometry. Our results show that important subsets of immune cells including human monocytes and dendritic cells express functional 5-HT1A and that its activation is associated with anti-inflammatory signaling. Furthermore, application of the probe to the experimental autoimmune encephalomyelitis model of multiple sclerosis demonstrates its potential to detect the specific overexpression of the 5-HT1A receptor in CD4+ T cells. Accordingly, the probe reported herein represents a useful tool whose use can be extended to study the levels of 5-HT1A receptor in ex vivo samples of different immune system conditions.
  • Publication
    A Fluorescent Probe to Unravel Functional Features of Cannabinoid Receptor CB1 in Human Blood and Tonsil Immune System Cells
    (American Chemical Society (ACS), 2018-02-21) Martín Fontecha, María del Mar; Angelina Querencias, Alba; Rückert, Beate; Rueda Zubiaurre, Ainoa; Veen, Willem van de; Akdis, Mübeccel; Ortega Gutiérrez, Silvia; López Rodríguez, María Luz; Akdis, Cezmi A.; Palomares, Oscar; Martín De La Cruz, Leticia
    The human endogenous cannabinoid system (ECS) regulates key physiological processes and alterations in its signaling pathways, and endocannabinoid levels are associated with diseases such as neurological and neuropsychiatric conditions, cancer, pain and inflammation, obesity, and metabolic and different immune related disorders. Immune system cells express the G-protein coupled cannabinoid receptor 1 (CB1), but its functional role has not been fully understood, likely due to the lack of appropriate tools. The availability of novel tools to investigate the role of CB1 in immune regulation might contribute to identify CB1 as a potential novel therapeutic target or biomarker for many diseases. Herein, we report the development and validation of the first fluorescent small molecule probe to directly visualize and quantify CB1 in blood and tonsil immune cells by flow cytometry and confocal microscopy. We coupled the cannabinoid agonist HU210 to the fluorescent tag Alexa Fluor 488, generating a fluorescent probe with high affinity for CB1 and selectivity over CB2. We validate HU210-Alexa488 for the rapid, simultaneous, and reproducible identification of CB1 in human monocytes, T cells, and B cells by multiplexed flow cytometry. This probe is also suitable for the direct visualization of CB1 in tonsil tissues, allowing the in vivo identification of tonsil CB1-expressing T and B cells. This study provides the first fluorescent chemical tool to investigate CB1 expression and function in human blood and tonsil immune cells, which might well pave the way to unravel essential features of CB1 in different immune and ECS-related diseases.