Galectin-1: A Jack-of-all-trades in the resolution of acute and chronic inflammation

Regulatory signals provide negative input to immunologicalnetworks promoting resolution of acute andchronic inflammation. Galectin-1 (Gal-1), a member of afamily of evolutionarily conserved glycan-binding proteins,displays broad anti-inflammatory and proresolvingactivities by targeting multiple immune cell types. Withinthe innate immune compartment, Gal-1 acts as a resolutionassociatedmolecular pattern by counteracting the synthesisof proinflammatory cytokines, inhibiting neutrophiltrafficking, targeting eosinophil migration and survival,and suppressing mast cell degranulation. Likewise, thislectin controls T cell and B cell compartments by modulatingreceptor clustering and signaling, thus serving asa negative-regulatory checkpoint that reprograms cellularactivation, differentiation, and survival. In this review,we discuss the central role of Gal-1 in regulatoryprograms operating during acute inflammation, autoimmunediseases, allergic inflammation, pregnancy, cancer,and infection. Therapeutic strategies aimed at targetingGal-1?glycan interactions will contribute to overcomecancer immunosuppression and reinforce antimicrobialimmunity, whereas stimulation of Gal-1?driven immunoregulatorycircuits will help to mitigate exuberant inflammation.Fil: Sundblad, Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Morosi, Luciano Gastón. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Geffner, Jorge Raúl. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Microbiología; ArgentinaFil: Rabinovich, Gabriel Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentin

La restauración del conjunto monumental de Valdediós

Sensibilizar al alumno ante nuestro patrimonio histórico-artístico, su importancia dentro de nuestra cultura, su estado actual y recuperación. Proporcionar un estudio multidisciplinar a los profesores que motive a utilizar los recursos cercanos, en torno a un centro de interés: Valdediós. Promover el trabajo activo y lúdico de los alumnos que incentive su afán de búsqueda del conocimiento. Proporcionar ayuda pedagógica para estudiar el concepto de tiempo historico, adecuándolo a los diferentes niveles de aprendizaje. El proyecto de visitas escolares de la Escuela Taller de Valdediós trata de sensibilizar a la población del progresivo deterioro que muestra nuestro patrimonio y ante el que no se puede quedar impasible. Consta de 2 libretos: 1.'Una visita, un aprendizaje' en el que se incluyen los objetivos generales del proyecto, la metodología que organiza el trabajo didáctico a desarrollar con las guías en sus tres fases consecutivas antes, durante y después de la visita. Los objetivos a perseguir en cada nivel de enseñanza (ciclo medio, superior y Enseñanzas Medias) orientadores del proceso y por último las guías de trabajo en el que se descubre el eje de la investigación que llevaron a cabo los alumnos y el itinerario a desarrollar. 2. El libreto 'Los datos, el análisis' está destinado a completar la información que los alumnos registran durante la visita. En él se incluyen datos del medio físico donde se asienta el conjunto monumental, su historia, los estilos arquitectónicos de los edificios, los materiales utilizados, los oficios y las disciplinas que intervienen en la recuperación del patrimonio. Bibliografía. Se propone un método de trabajo activo y lúdico, es el alumno quien a través de la observación, recogida de datos y posterior consulta y ampliación de los mismos, construye su aprendizaje, al mismo tiempo que desarrolla la capacidad de relación social. Las guías de trabajo se centran en el estudio del recinto de Valdediós, enfocado de distinto modo para cada nivel de aprendizaje: Ciclo medio: observación y estudio de San Salvador. Ciclo superior: se propone la comparación de ambos edificios para deducir hipótesis que se comprobarán en el aula. Enseñanzas Medias: verificar hipótesis y conocimientos que poseen sobre distintos periodos históricos y su producción artística; se intenta desarrollar la autonomía en su proceso investigador. Se presentan los objetivos para cada nivel, así como las actividades apoyadas en dibujos, fotografías, esquemas, planos, documentos, prácticas de laboratorio, así como un material complementario en el que se dan datos sobre su historia, arquitectura, recuperación y vocabulario utilizado.AsturiasES

Hypothyroidism-associated immunosuppression involves induction of galectin1-producing regulatory T cells

Abstract: Hypothyroidism exerts deleterious effects on immunity, but the precise role of the hypothalamicpituitary-thyroid (HPT) axis in immunoregulatory and tolerogenic programs is barely understood. Here we investigated the mechanisms underlying hypothyroid-related immunosuppression by examining the regulatory role of components of the HPT axis. We first analyzed lymphocyte activity in mice overexpressing the TRH gene (Tg-Trh). T cells from TgTrh showed increased proliferation than wild type (WT) euthyroid mice in response to polyclonal activation. The release of Th1 proinflammatory cytokines was also increased in TgTrh, and TSH levels correlated with T cell proliferation. To gain further mechanistic insights into hypothyroidism-related immunosuppression, we evaluated T cell subpopulations in lymphoid tissues of hypothyroid and control mice. No differences were observed in CD3/CD19 or CD4/CD8 ratios between these strains. However, the frequency of regulatory T cells (Tregs) was significantly increased in hypothyroid mice, and not in Tg-Trh mice. Accordingly, in vitro Tregs differentiation was more pronounced in naïve T cells isolated from hypothyroid mice. Since Tregs overexpress galectin-1 (Gal-1) and mice lacking this lectin (Lgals1-/-) show reduced Treg function, we investigated the involvement of this immunoregulatory lectin in the control of Tregs in settings of hypothyroidism. Increased T lymphocyte reactivity and reduced frequency of Tregs were found in hypothyroid Lgals1-/- mice when compared to hypothyroid WT animals. This effect was rescued by addition of recombinant Gal-1. Finally, increased expression of Gal-1 was found in Tregs purified from hypothyroid WT mice compared with their euthyroid counterpart. Thus, a substantial increase in the frequency and activity of Gal-1-expressing Tregs underlies immunosuppression associated with hypothyroid conditions, with critical implications in immunopathology, metabolic disorders, and cancer

Monosaccharide Derivatives with Low-Nanomolar Lectin Affinity and High Selectivity Based on Combined Fluorine-Amide, Phenyl-Arginine, Sulfur-π, and Halogen Bond Interactions

The design of small and high-affinity lectin inhibitors remains a major challenge because the natural ligand binding sites of lectin are often shallow and have polar character. Herein we report that derivatizing galactose with un-natural structural elements that form multiple non-natural lectin-ligand interactions (orthogonal multipolar fluorine-amide, phenyl-arginine, sulfur-π, and halogen bond) can provide inhibitors with extraordinary affinity (low nanomolar) for the model lectin, galectin-3, which is more than five orders of magnitude higher than the parent galactose; moreover, is selective over other galectins

Multiple concomitant mechanisms contribute to low platelet count in patients with immune thrombocytopenia

Abstract Mechanisms leading to low platelet count in immune thrombocytopenia (ITP) involves both decreased production and increased destruction of platelet. However, the contribution of these pathologic mechanisms to clinical outcome of individual patients is uncertain. Here we evaluated different pathogenic mechanisms including in vitro megakaryopoiesis, platelet/megakaryocyte (MK) desialylation and MK apoptosis, and compared these effects with thrombopoyesis and platelet apoptosis in the same cohort of ITP patients. Normal umbilical cord blood-CD34+ cells, mature MK derived cells or platelets were incubated with plasma from ITP patients. Despite inhibition of thrombopoiesis previously observed, megakaryopoiesis was normal or even increased. Plasma from ITP patients affected the sialylation pattern of control platelets and this effect occurred concomitantly with apoptosis in 35% ITP samples. However, none of these abnormalities were observed in control MKs incubated with ITP plasma. Addition of mononuclear cells as immune effectors did not lead to phosphatidylserine exposure in MK, ruling out an antibody-mediated cytotoxic effect. These results suggest that both desialylation and apoptosis may be relevant mechanisms leading to platelet destruction although, they do not interfere with MK function. Analysis of these thrombocytopenic factors in individual patients showed no specific distribution pattern. However, the presence of circulating antiplatelet autoantibodies was associated with higher incidence of abnormalities. In conclusion, the causes of thrombocytopenia are multifactorial and may occur together, providing a rational basis for the use of combination therapies targeting concomitant ITP mechanisms in patients with refractory disease

The thyroid status reprograms T cell lymphoma growth and modulates immune cell frequencies

Abstract: In spite of considerable evidence on the regulation of immunity by thyroid hormones, the impact of the thyroid status in tumor immunity is poorly understood. Here, we evaluated the antitumor immune responses evoked in mice with different thyroid status (euthyroid, hyperthyroid, and hypothyroid) that developed solid tumors or metastases after inoculation of syngeneic T lymphoma cells. Hyperthyroid mice showed increased tumor growth along with increased expression of cell cycle regulators compared to hypothyroid and control tumor-bearing mice. However, hypothyroid mice showed a higher frequency of metastases than the other groups. Hyperthyroid mice bearing tumors displayed a lower number of tumor-infiltrating T lymphocytes, lower percentage of functional IFN-γ-producing CD8+ T cells, and higher percentage of CD19+ B cells than euthyroid tumor-bearing mice. However, no differences were found in the distribution of lymphocyte subpopulations in tumor-draining lymph nodes (TDLNs) or spleens among different experimental groups. Interestingly, hypothyroid TDLN showed an increased percentage of regulatory T (Treg) cells, while hyperthyroid mice displayed increased number and activity of splenic NK cells, which frequency declined in spleens from hypothyroid mice. Moreover, a decreased number of splenic myeloid-derived suppressor cells (MDSCs) were found in tumor-bearing hyperthyroid mice as compared to hypothyroid or euthyroid mice. Additionally, hyperthyroid mice showed increased cytotoxic activity, which declined in hypothyroid mice. Thus, low levels of intratumoral cytotoxic activity would favor tumor local growth in hyperthyroid mice, while regional and systemic antitumor response may contribute to tumor dissemination in hypothyroid animals. Our results highlight the importance of monitoring the thyroid status in patients with T cell lymphomas

Control of intestinal inflammation by glycosylation-dependent lectin-driven immunoregulatory circuits

Diverse immunoregulatory circuits operate to preserve intestinal homeostasis and prevent inflammation. Galectin-1 (Gal1), a β-galactoside-binding protein, promotes homeostasis by reprogramming innate and adaptive immunity. Here, we identify a glycosylation-dependent "on-off" circuit driven by Gal1 and its glycosylated ligands that controls intestinal immunopathology by targeting activated CD8⁺ T cells and shaping the cytokine profile. In patients with inflammatory bowel disease (IBD), augmented Gal1 was associated with dysregulated expression of core 2 β6-N-acetylglucosaminyltransferase 1 (C2GNT1) and α(2,6)-sialyltransferase 1 (ST6GAL1), glycosyltransferases responsible for creating or masking Gal1 ligands. Mice lacking Gal1 exhibited exacerbated colitis and augmented mucosal CD8⁺ T cell activation in response to 2,4,6-trinitrobenzenesulfonic acid; this phenotype was partially ameliorated by treatment with recombinant Gal1. While C2gnt1-/- mice exhibited aggravated colitis, St6gal1-/- mice showed attenuated inflammation. These effects were associated with intrinsic T cell glycosylation. Thus, Gal1 and its glycosylated ligands act to preserve intestinal homeostasis by recalibrating T cell immunity.Facultad de Ciencias ExactasInstituto de Estudios Inmunológicos y Fisiopatológico