RESUMO
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
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.
Assuntos
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
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.
Assuntos
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
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.
Assuntos
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.
Assuntos
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
Foi realizado um estudo aberto, näo comparativo, com o Misoprostol, prostaglandina sintética no tipo E1, na terapêutica de 30 pacientes portadores de osteoartrose em uso de Naproxen e que, concomitantemente, exibiram manifestaçöes clínicas relativas ao trato gastrintestinal superior. Esses pacientes receberam Misoprostol na dose de 200 mcg, três vezes ao dia, administrados simultanemante com sua dose diária do antiinflamatório näo hormonal. O tempo de observaçäo máxima seria de oito semanas, com avaliaçöes clínicas intermediárias sendo efetuadas no final das 2ª, 4ª e 8ª semanas. Dezenove (19) pacientes (63,3%), já ao final da 2ª semana, relataram acentuadas diminuiçöes digestivas enquanto que, mais 8 pacientes (26,7%) totalizando 27 (90%) ao final da 4ª semana, exibiam tal melhora. Apenas dois pacientes acusaram efeitos colaterais significativos, porém näo foram demonstradas alteraçöes de monta nos dados vitais nem nos exames laboratoriais executados. Os autores concluem pela validade do uso de Misoprostol na atenuaçäo dos sintomas gastrintestinais superiores de pacientes artrósicos em uso simultâneo de Naproxen