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Immune checkpoint blockers improve the overall survival of a limited number of patients among different cancers. Identifying pathways that influence the immunological and clinical response to treatment is critical to improve the therapeutic efficacy and predict clinical responses. Recently, a key role has been assigned to innate immune mechanisms in checkpoint blockade-driven anti-tumor responses. However, inflammatory pathways can both improve and impair anti-tumor immunity. In this review, we discuss how different inflammatory pathways, particularly inflammasome activation, can influence the clinical outcome of immune checkpoint blockers. Inflammasome activation may reinforce anti-tumor immunity by boosting CD8+ T cell priming as well as by enhancing T helper type 17 (Th17) responses. In particular, we focus on the modulation of the cation channel transmembrane protein 176B (TMEM176B) and the ectonucleotidase CD39 as potential targets to unleash inflammasome activation leading to reinforced anti-tumor immunity and improved efficacy of immune checkpoint blockers. Future studies should be aimed at investigating the mechanisms and cell subsets involved in inflammasome-driven anti-tumor responses.
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Apirase , Inflamassomos/imunologia , Proteínas de Membrana , Proteínas de Neoplasias , Neoplasias , Animais , Apirase/antagonistas & inibidores , Apirase/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Humanos , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/imunologia , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/imunologia , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/patologia , Células Th17/imunologia , Células Th17/patologiaRESUMO
The aim of this work was to combine our previously published results with our new data to show how galectin-3 (Gal-3) controls myelin integrity and function, promotes oligodendroglial cell differentiation, and regulates microglial responses to limit cuprizone- (CPZ)-induced demyelination and foster remyelination. In this study, 8-week-old Gal-3-deficient (Lgals3 -/-) and wild type (WT) mice were fed a diet containing 0.2 % CPZ w/w for 6 weeks, after which CPZ was withdrawn in order to allow remyelination. Our results show that remyelination was less efficient in Lgals3 -/- than in WT mice. Electron microscopic images from remyelinated sections in Lgals3 -/- mice revealed collapsed axons with a defective myelin wrap, while remyelinated WT mice had normal axons without relevant myelin wrap disruption. MMP-3 expression increased during remyelination in WT but not in Lgals3 -/- mice. The number of CD45+, TNFα+ and TREM-2b+ cells decreased only in WT mice only, with no alterations in Lgals3 -/- mice during demyelination and remyelination. Therefore, Gal-3 influences remyelination by mechanisms involving the tuning of microglial cells, modulation of MMP activity, and changes in myelin architecture.
Assuntos
Astrócitos/patologia , Doenças Desmielinizantes/genética , Galectina 3/genética , Microglia/patologia , Oligodendroglia/patologia , Regeneração/genética , Animais , Astrócitos/metabolismo , Axônios/metabolismo , Axônios/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Diferenciação Celular , Cuprizona , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/patologia , Doenças Desmielinizantes/reabilitação , Galectina 3/deficiência , Regulação da Expressão Gênica , Proteína Glial Fibrilar Ácida/genética , Proteína Glial Fibrilar Ácida/metabolismo , Antígenos Comuns de Leucócito/genética , Antígenos Comuns de Leucócito/metabolismo , Masculino , Metaloproteinase 3 da Matriz/genética , Metaloproteinase 3 da Matriz/metabolismo , Camundongos , Camundongos Knockout , Microglia/metabolismo , Proteína Básica da Mielina/genética , Proteína Básica da Mielina/metabolismo , Oligodendroglia/metabolismo , Fagocitose , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Dendritic cell (DC) cancer vaccines have shown limited clinical benefit. Thus, the identification of signals and molecular pathways that potentiate the immunogenicity of DCs has become a major challenge in cancer research. Our studies demonstrate that triiodothyronine endows DCs with enhanced ability to stimulate cytotoxic T-cell responses with implications in DC-based immunotherapy.
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UNLABELLED: 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. KEY MESSAGES: T cell lymphoma phenotype is paradoxically influenced by thyroid status. Hyperthyroidism favors tumor growth and hypothyroidism rises tumor dissemination. Thyroid status affects the distribution of immune cell types in the tumor milieu. Thyroid status also modifies the nature of local and systemic immune responses.
Assuntos
Imunomodulação , Linfoma de Células T/imunologia , Linfoma de Células T/metabolismo , Doenças da Glândula Tireoide/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Hipertireoidismo/metabolismo , Hipotireoidismo/metabolismo , Contagem de Linfócitos , Linfoma de Células T/complicações , Linfoma de Células T/patologia , Camundongos , Metástase Neoplásica , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Doenças da Glândula Tireoide/complicações , Hormônios Tireóideos/metabolismo , Hormônios Tireóideos/farmacologia , Carga Tumoral , Microambiente Tumoral/imunologiaRESUMO
Following spinal cord injury (SCI), semaphorin 3A (Sema3A) prevents axonal regeneration through binding to the neuropilin-1 (NRP-1)/PlexinA4 receptor complex. Here, we show that galectin-1 (Gal-1), an endogenous glycan-binding protein, selectively bound to the NRP-1/PlexinA4 receptor complex in injured neurons through a glycan-dependent mechanism, interrupts the Sema3A pathway and contributes to axonal regeneration and locomotor recovery after SCI. Although both Gal-1 and its monomeric variant contribute to de-activation of microglia, only high concentrations of wild-type Gal-1 (which co-exists in a monomer-dimer equilibrium) bind to the NRP-1/PlexinA4 receptor complex and promote axonal regeneration. Our results show that Gal-1, mainly in its dimeric form, promotes functional recovery of spinal lesions by interfering with inhibitory signals triggered by Sema3A binding to NRP-1/PlexinA4 complex, supporting the use of this lectin for the treatment of SCI patients.
Assuntos
Galectina 1/metabolismo , Neuropilina-1/metabolismo , Regeneração , Traumatismos da Medula Espinal/metabolismo , Animais , Axônios/metabolismo , Axônios/patologia , Galectina 1/genética , Humanos , Lectinas/metabolismo , Lectinas/uso terapêutico , Camundongos Knockout , Polissacarídeos/metabolismo , Semaforina-3A/genética , Semaforina-3A/metabolismo , Medula Espinal/crescimento & desenvolvimento , Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia , Traumatismos da Medula Espinal/terapiaRESUMO
Galectins are evolutionarily conserved glycan-binding proteins with pleiotropic roles in innate and adaptive immune responses. Galectin-3 has been implicated in several immunological processes as well as in pathogen recognition through specific binding to glycosylated receptors on the surface of host cells or microorganisms. In spite of considerable evidence supporting a role for galectin-3 in host-pathogen interactions, the relevance of this lectin in the regulation of the host defence mechanisms in vivo is poorly understood. In this study, we analysed the impact of galectin-3 deficiency during infection with three distinct species of rodent malaria parasites, Plasmodium yoelii 17XNL, Plasmodium berghei ANKA and Plasmodium chabaudi AS. We found that galectin-3 deficiency showed a marginal effect on the course of parasitaemia during P. chabaudi infection, but did not alter the course of parasitaemia during P. berghei infection. However, lack of galectin-3 significantly reduced P. yoelii parasitaemia. This reduced parasitaemia in Lgals3(-/-) mice was consistent with higher titres of anti-P. yoelii MSP1(19) IgG2b isotype antibodies when compared with their wild-type counterparts. Our results reflect the complexity and singularity of host-pathogen interactions, indicating a species-specific role of endogenous galectin-3 in the control of parasite infections and the modulation of antibody responses.
Assuntos
Galectina 3/imunologia , Interações Hospedeiro-Patógeno , Malária/patologia , Plasmodium berghei/patogenicidade , Plasmodium chabaudi/patogenicidade , Plasmodium yoelii/patogenicidade , Animais , Anticorpos Antiprotozoários/sangue , Modelos Animais de Doenças , Feminino , Galectina 3/deficiência , Imunoglobulina G/sangue , Malária/imunologia , Malária/parasitologia , Camundongos , Camundongos Knockout , Parasitemia/imunologia , Parasitemia/parasitologia , Parasitemia/patologia , Plasmodium berghei/imunologia , Plasmodium chabaudi/imunologia , Plasmodium yoelii/imunologiaRESUMO
Intestinal epithelial cells serve as mechanical barriers and active components of the mucosal immune system. These cells migrate from the crypt to the tip of the villus, where different stimuli can differentially affect their survival. Here we investigated, using in vitro and in vivo strategies, the role of galectin-1 (Gal-1), an evolutionarily conserved glycan-binding protein, in modulating the survival of human and mouse enterocytes. Both Gal-1 and its specific glyco-receptors were broadly expressed in small bowel enterocytes. Exogenous Gal-1 reduced the viability of enterocytes through apoptotic mechanisms involving activation of both caspase and mitochondrial pathways. Consistent with these findings, apoptotic cells were mainly detected at the tip of the villi, following administration of Gal-1. Moreover, Gal-1-deficient (Lgals1(-/-)) mice showed longer villi compared with their wild-type counterparts in vivo. In an experimental model of starvation, fasted wild-type mice displayed reduced villi and lower intestinal weight compared with Lgals1(-/-) mutant mice, an effect reflected by changes in the frequency of enterocyte apoptosis. Of note, human small bowel enterocytes were also prone to this pro-apoptotic effect. Thus, Gal-1 is broadly expressed in mucosal tissue and influences the viability of human and mouse enterocytes, an effect which might influence the migration of these cells from the crypt, the integrity of the villus and the epithelial barrier function.
Assuntos
Células Epiteliais/citologia , Galectina 1/metabolismo , Intestino Delgado/citologia , Intestino Delgado/metabolismo , Polissacarídeos/metabolismo , Animais , Morte Celular , Proliferação de Células , Sobrevivência Celular , Células Epiteliais/metabolismo , Galectina 1/deficiência , Galectina 1/genética , Humanos , Masculino , Camundongos , Camundongos KnockoutRESUMO
Galectins control critical pathophysiological processes, including the progression and resolution of central nervous system (CNS) inflammation. In spite of considerable progress in dissecting their role within lymphoid organs, their functions within the inflamed CNS remain elusive. Here, we investigated the role of galectin-glycan interactions in the control of oligodendrocyte (OLG) differentiation, myelin integrity and function. Both galectin-1 and -3 were abundant in astrocytes and microglia. Although galectin-1 was abundant in immature but not in differentiated OLGs, galectin-3 was upregulated during OLG differentiation. Biochemical analysis revealed increased activity of metalloproteinases responsible for cleaving galectin-3 during OLG differentiation and modulating its biological activity. Exposure to galectin-3 promoted OLG differentiation in a dose- and carbohydrate-dependent fashion consistent with the 'glycosylation signature' of immature versus differentiated OLG. Accordingly, conditioned media from galectin-3-expressing, but not galectin-3-deficient (Lgals3(-/-)) microglia, successfully promoted OLG differentiation. Supporting these findings, morphometric analysis showed a significant decrease in the frequency of myelinated axons, myelin turns (lamellae) and g-ratio in the corpus callosum and striatum of Lgals3(-/-) compared with wild-type (WT) mice. Moreover, the myelin structure was loosely wrapped around the axons and less smooth in Lgals3(-/-) mice versus WT mice. Behavior analysis revealed decreased anxiety in Lgals3(-/-) mice similar to that observed during early demyelination induced by cuprizone intoxication. Finally, commitment toward the oligodendroglial fate was favored in neurospheres isolated from WT but not Lgals3(-/-) mice. Hence, glial-derived galectin-3, but not galectin-1, promotes OLG differentiation, thus contributing to myelin integrity and function with critical implications in the recovery of inflammatory demyelinating disorders.
Assuntos
Diferenciação Celular , Bainha de Mielina/fisiologia , Oligodendroglia/citologia , Animais , Astrócitos/citologia , Astrócitos/metabolismo , Axônios/metabolismo , Comportamento Animal , Células Cultivadas , Cuprizona/toxicidade , Galectina 1/metabolismo , Galectina 3/deficiência , Galectina 3/genética , Galectina 3/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Microglia/citologia , Microglia/metabolismo , Bainha de Mielina/genética , Bainha de Mielina/metabolismo , Oligodendroglia/metabolismo , Polissacarídeos/metabolismo , Regiões Promotoras Genéticas , Ligação Proteica , Ratos , Ratos WistarRESUMO
A breakdown in intestinal homeostasis results in inflammatory bowel diseases including coeliac disease and allergy. Galectins, evolutionarily conserved beta-galactoside-binding proteins, can modulate immune-epithelial cell interactions by influencing immune cell fate and cytokine secretion. In this study we investigated the glycosylation signature, as well as the regulated expression of galectin-1 and -3 in human duodenal samples of allergic and non-allergic children. Whereas galectin-1 was predominantly localized in the epithelial compartment (epithelial cells and intraepithelial lymphocytes) and the underlying lamina propria (T cells, macrophages and plasma cells), galectin-3 was mainly expressed by crypt epithelial cells and macrophages in the lamina propria. Remarkably, expression of these galectins was not significantly altered in allergic versus non-allergic patients. Investigation of the glycophenotype of the duodenal inflammatory microenvironment revealed substantial alpha2-6-linked sialic acid bound to galactose in lamina propria plasma cells, macrophages and intraepithelial lymphocytes and significant levels of asialo core 1 O-glycans in CD68+ macrophages and enterocytes. Galectin-1 preferentially bound to neutrophils, plasma cells and enterocytes, while galectin-3 binding sites were mainly distributed on macrophages and intraepithelial lymphocytes. Notably, galectin-3, but not galectin-1 binding, was substantially increased in intraepithelial gut lymphocytes of allergic patients compared to non-allergic subjects, suggesting a potential role of galectin-3-glycan interactions in shaping epithelial-immune cell connections during allergic inflammatory processes.
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Duodeno/imunologia , Galectina 3/metabolismo , Linfócitos/metabolismo , Hipersensibilidade a Leite/imunologia , Sítios de Ligação , Pré-Escolar , Duodeno/química , Feminino , Galectina 1/análise , Galectina 1/metabolismo , Galectina 3/análise , Humanos , Lactente , Masculino , Hipersensibilidade a Leite/etiologia , Aglutinina de Amendoim/metabolismo , Lectinas de Plantas/metabolismo , Proteínas Inativadoras de Ribossomos/metabolismoRESUMO
Inflammation is a critical process for eliminating pathogens, but can lead to serious deleterious effects if left unchecked. Identifying the endogenous factors that control immune tolerance and inflammation is a key goal in the field of immunology. Galectins, a family of endogenous lectins with affinity for beta-galactoside-containing oligosaccharides, are expressed by several cells of the immune system and tissue-resident stromal cells. According to their architecture, this family of glycan-binding proteins is classified in those containing one-carbohydrate-recognition domain (CRD) (proto-type), those containing two-CRD joined by a linker non-lectin domain (tandem-repeat) and those that have one-CRD attached to an N-terminal peptide (chimera-type). Accumulating evidence indicates that galectins play critical regulatory roles in immune cell response and homeostasis. In this review, we summarize recent developments in our understanding of the galectins' roles within different immune cell compartments, and in the broader context of the inflammatory microenvironments. In particular we illustrate the immunoregulatory role of three representative members of each galectin subfamily: galectin-1, -3 and -9. This body of knowledge, documenting the coming of age of galectins as potential immunosuppressive agents or targets for anti-inflammatory drugs, represents a sound basis to further explore their potential as novel therapies for autoimmune diseases, chronic inflammation and cancer.
Assuntos
Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Modelos Animais de Doenças , Galectinas/fisiologia , Mediadores da Inflamação/fisiologia , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/metabolismo , Animais , HumanosRESUMO
Galectins are a taxonomically widespread family of glycan-binding proteins, defined by at least one conserved carbohydrate-recognition domain with a canonical amino acid sequence and affinity for beta-galactosides. Because of their anti-adhesive as well as pro-adhesive extracellular functions, galectins appear to be a novel class of adhesion-modulating proteins collectively known as matricellular proteins (which include thrombospondin, SPARC, tenascin, hevin, and disintegrins). Accordingly, galectins can display de-adhesive effects when presented as soluble proteins to cells in a strong adhesive state. In this context, the de-adhesive properties of galectins should be considered as physiologically relevant as the proadhesive effects of these glycan-binding proteins. This article focuses on the roles of mammalian galectins in cell adhesion, spreading, and migration, and the crossregulation of these functions. Although careful attention should be paid when examining individual galectin functions due to overlapping distributions, these intriguing glycan-binding proteins offer promising possibilities for the treatment and intervention of a wide variety of pathological processes, including cancer, inflammation, and autoimmunity.
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Movimento Celular , Galectinas/metabolismo , Polissacarídeos/metabolismo , Animais , Adesão Celular , Sobrevivência Celular , HumanosRESUMO
Immune cell homoeostasis is attributed to multiple distinct safety valves that are interconnected and intervene at defined checkpoints of the life cycle of immunocytes to guarantee clonal expansion and functional inactivation of self-reactive potentially autoaggressive lymphocytes. Galectins, animal lectins defined by shared consensus amino acid sequence and affinity for beta-galactose containing oligosaccharides, are found on various cells of the immune system, and their expression is associated with the differentiation and activation status of these cells. Over the past few years, galectins have been implicated in the regulation of many aspects of T cell physiology such as cell activation, differentiation, and apoptosis. In addition, a growing body of experimental evidence indicates that galectins may play critical roles in the modulation of chronic inflammatory disorders, autoimmunity, and cancer. Given the increased interest of immunologists in this field, the growing body of information raised during the past few years and the potential use of galectins as novel anti-inflammatory agents or targets for immunosuppressive drugs, we will summarise recent advances on the role of galectins in different aspects of T cell physiology and their impact in the development and/or resolution of chronic inflammatory disorders, autoimmunity, and cancer.
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Galectinas/imunologia , Inflamação/imunologia , Linfócitos T/imunologia , Animais , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/imunologia , Doença Crônica , Galectinas/uso terapêutico , Humanos , Inflamação/tratamento farmacológico , Ativação Linfocitária/imunologia , RatosRESUMO
Recent evidence has implicated galectins, a family of evolutionarily conserved carbohydrate-binding proteins, as regulators of immune cell homeostasis and host-pathogen interactions. Galectins operate at different levels of innate and adaptive immune responses, by modulating cell survival and cell activation or by influencing the Th1/Th2 cytokine balance. Furthermore, galectins may contribute to host-pathogen recognition and may serve as receptors for specific interactions of pathogens with their insect vectors. Here we will explore the influence of galectins in immunological processes relevant to microbial infection and will summarize exciting recent work related to the specific interactions between galectins and their glycoconjugate ligands as critical determinants of pathogen recognition. Understanding the role of galectin-sugar interactions during the course of microbial infections might contribute to defining novel targets for disease prevention and immune intervention.
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Galectinas/imunologia , Infecções/imunologia , Animais , Apoptose , Sobrevivência Celular , Citocinas/imunologia , Citocinas/metabolismo , Galectinas/química , Galectinas/metabolismo , Glicoconjugados/metabolismo , Homeostase , Humanos , Imunidade Inata , Insetos Vetores/imunologia , Ativação Linfocitária , Linfócitos/imunologiaRESUMO
Galectins are a family of structurally related carbohydrate-binding proteins, which are defined by their affinity for poly-N-acetyllactosamine-enriched glycoconjugates and sequence similarities in the carbohydrate recognition domain. Galectin-1, a member of this family, contributes to different events associated with cancer biology, including tumour transformation, cell cycle regulation, apoptosis, cell adhesion, migration and inflammation. In addition, recent evidence indicates that galectin-1 contributes to tumour evasion of immune responses. Given the increased interest of tumour biologists and clinical oncologists in this field and the potential use of galectins as novel targets for anticancer drugs, we summarise here recent advances about the role of galectin-1 in different events of tumour growth and metastasis.
Assuntos
Apoptose , Transformação Celular Neoplásica , Galectina 1/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/fisiopatologia , Adesão Celular , Proliferação de Células , Humanos , InflamaçãoRESUMO
Apoptosis of cytotoxic T lymphocytes by herpes simplex virus type-1 (HSV-1) has been reported to be a relevant mechanism of viral immune evasion. Galectin-1 (Gal-1), an endogenous lectin involved in T-cell apoptosis, has recently gained considerable attention as a novel mechanism of tumor-immune evasion. Here we investigated whether infection of cells with HSV-1 can modulate the expression of Gal-1. Results show that pro-apoptotic Gal-1, but not Gal-3, is remarkably up-regulated in cell cultures infected with HSV-1. In addition, this protein is secreted to the extracellular milieu, where it contributes to apoptosis of activated T cells in a carbohydrate-dependent manner. Since many viruses have evolved mechanisms to counteract the antiviral response raised by the infected host, our results suggest that HSV-1 may use galectin-1 as a weapon to kill activated T cells and evade specific immune responses.
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Apoptose/fisiologia , Galectina 1/biossíntese , Regulação da Expressão Gênica/fisiologia , Herpes Simples/patologia , Herpesvirus Humano 1 , Linfócitos T/patologia , Animais , Western Blotting , Chlorocebus aethiops , Eletroforese em Gel de Poliacrilamida , Células Epiteliais/patologia , Técnica Indireta de Fluorescência para Anticorpo , Galectina 1/genética , Galectina 3/genética , Galectina 3/fisiologia , Humanos , Tolerância Imunológica , Células VeroRESUMO
Inflammation involves the sequential activation of signalling pathways leading to the production of both pro-inflammatory and anti-inflammatory mediators. Galectins constitute a family of structurally related beta-galactoside-binding proteins, which are defined by their affinity for poly-N-acetyllactosamine-enriched glycoconjugates and sequence similarities in the carbohydrate recognition domain. By crosslinking specific glycoconjugates, different members of the galectin family behave as pro-inflammatory or anti-inflammatory agents, acting at different levels of acute and chronic inflammatory responses. Recent studies highlighted immunomodulatory roles for galectins in vivo in several experimental models of chronic inflammation, suggesting that these carbohydrate-binding proteins may be potential targets for the design of a novel generation of anti-inflammatory agents. In this study, we review recent advances on the role of galectins in the initiation, amplification and resolution of the inflammatory response. In particular, we examine the influence of individual members of this family in regulating cell adhesion, migration, chemotaxis, antigen presentation, immune cell activation and apoptosis. From a better understanding of the molecular basis of galectin-induced immune regulation, we may become able to exploit the potential of these sugar-binding proteins and their glycoligands as suitable therapeutic agents in acute and chronic inflammatory disorders.
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Galectinas/imunologia , Galectinas/fisiologia , Inflamação/etiologia , Animais , Apresentação de Antígeno , Apoptose , Autoimunidade , Metabolismo dos Carboidratos , Comunicação Celular , Diferenciação Celular , Divisão Celular , Citocinas/fisiologia , Galectinas/farmacologia , Doença Enxerto-Hospedeiro/tratamento farmacológico , Humanos , Hipersensibilidade/etiologia , Imunidade Inata , Fatores Imunológicos/farmacologia , Imunossupressores/farmacologia , Infecções/tratamento farmacológico , Inflamação/imunologia , Inflamação/fisiopatologia , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/fisiologia , Modelos Imunológicos , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Transdução de Sinais , Linfócitos T/citologia , Linfócitos T/imunologiaRESUMO
Hyperactivity of the hypothalamic pituitary adrenal (HPA) axis in patients with major depression is one of the most consistent findings in biological psychiatry. Experimental data support the idea that glucocorticoid-mediated feedback via glucocorticoid receptors (GR) is impaired in major depression. The aim of the present work was to assess the putative changes in GR density of peripheral blood mononuclear cells (PBMCs) in a group of patients with major depression and to determine modulation of these GR sites by antidepressant treatment. In addition, susceptibility of PBMCs to glucocorticoid effects was also studied using a functional end-point analysis in vitro, such as cortisol inhibition of mitogen-induced lymphocyte proliferation. Cortisol levels were also measured before and after dexamethasone suppression test (DST). The results showed a decrease in GR density in depressed patients compared with healthy subjects, mainly in those patients that showed basal cortisol levels in the upper normal range and were refractory to DST. Regarding the functional significance of this variation, two representative groups emerged from our study: a) free-medication patients with GR function comparable to healthy controls, and b) patients showing diminished GR activity. These results suggest a lack of relationship between GR density and cortisol-induced inhibition of lymphocyte proliferation. Patients treated with different antidepressant drugs showed a marked increase in the number of GR sites per cell compared to non-treated. Interestingly, this increase was even higher than in normal subjects. Hence, restoration of GR density after an efficient antidepressant treatment could be an index of an effective modulatory action of drugs on GR expression and highlights the possibility that GR levels might be used as markers of a successful treatment.
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Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Receptores de Glucocorticoides/efeitos dos fármacos , Adulto , Análise de Variância , Antidepressivos/farmacocinética , Transtorno Depressivo Maior/fisiopatologia , Dexametasona , Quimioterapia Combinada , Feminino , Humanos , Hidrocortisona/sangue , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/fisiopatologia , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/fisiologia , Masculino , Inventário de Personalidade , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/fisiopatologia , Receptores de Glucocorticoides/fisiologia , Valores de Referência , Resultado do TratamentoRESUMO
Galectin-1, a beta-galactoside-binding protein expressed at sites of T-cell activation and immune privilege, has shown specific immunosuppressive properties. Because of the implications of this protein in T-cell tolerance and its potential use to avoid graft rejection, we investigated the immunosuppressive effects of galectin-1 in the course of the human allogenic T-cell response. Galectin-1 induced a dose- and carbohydrate-dependent inhibition of the allogenic T-cell response. Addition of galectin-1 to alloreactive lymphocytes resulted in significant apoptosis of CD45R0-positive cells. This negative regulatory effect was accompanied by caspase activation, Bcl-2 downregulation and was prevented by addition of exogenous IL-2. In addition, a significant decrease of IFN-gamma production was detected in the non-apoptotic cell population, following exposure of alloreactive lymphocytes to galectin-1. Moreover, the immunosuppressive activity of this protein did not involve TGF-beta-mediated mechanisms. Since galectin-1 is expressed by activated T cells and could be acting by an autocrine negative loop to control human T-cell reactivity, we finally examined the regulated expression of this protein throughout the allogenic T-cell response. Expression of endogenous galectin-1 was detected at 24 h of cell culture, reaching its maximal levels after 72 h of allostimulation. The present study sets the basis for a potential use of galectin-1 as a selective immunosuppressive agent to limit T-cell-mediated reactivity during the effector phase of the alloimmune response.
Assuntos
Apoptose , Galectina 1/farmacologia , Imunossupressores/farmacologia , Linfócitos T/efeitos dos fármacos , Adulto , Carboidratos/imunologia , Caspases/metabolismo , Células Cultivadas , Relação Dose-Resposta a Droga , Galectina 1/biossíntese , Humanos , Interferon gama/metabolismo , Interleucina-2/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Fator de Crescimento Transformador beta/metabolismoRESUMO
Galectin-1 is a beta-galactoside-binding protein with potent anti-inflammatory and immunoregulatory effects. However, its expression and function have not been assessed in the context of an infectious disease. The present study documents, for the first time, the regulated expression of galectin-1 in the context of an infectious process and its influence in the modulation of macrophage microbicidal activity and survival. A biphasic modulation in parasite replication and cell viability was observed when macrophages isolated from Trypanosoma cruzi-infected mice were exposed to increasing concentrations of galectin-1. While low concentrations of this protein increased parasite replication and did not affect macrophage survival, higher inflammatory doses of galectin-1 were able to commit cells to apoptosis and inhibited parasite replication. Furthermore, galectin-1 at its lowest concentration was able to down-regulate critical mediators for parasite killing, such as interleukin 12 (IL-12) and nitric oxide, while it did not affect IL-10 secretion. Finally, endogenous galectin-1 was found to be up-regulated and secreted by the J774 macrophage cell line cultured in the presence of trypomastigotes. This result was extended in vivo by Western blot analysis, flow cytometry, and reverse transcription-PCR using macrophages isolated from T. cruzi-infected mice. This study documents the first association between galectin-1's immunoregulatory properties and its role in infection and provides new clues to the understanding of the mechanisms implicated in host-parasite interactions during Chagas' disease and other parasite infections.