Galectins in parasite infection and allergic inflammation

Galectins are increasingly recognised as important immunological mediators of homeostasis and disease regulation. This paper gives an overview of current knowledge of galectin involvement in parasite infection and allergic inflammation, two very different but immunologically linked phenomena. Galectins are produced by both the parasite and the host and appear to be intimately involved in parasite establishment, as well as directing the course of infection and the immune response. Host galectins have also been shown to be active participants in the recruitment of cells to sites of inflammation and modulating the effector function of mast cells, neutrophils and eosinophils. Moreover, the ability of galectins to induce differential expression of cytokine genes in leukocytes suggests that they are able to direct the nature of an adaptive immune response, in particular towards a T2-type allergic response. Published in 2004.     

Mammalian galectins: Structure,carbohydrate specificity,and functions

Galectins are a family of beta-galactoside binding lectins, homological by a sequence of the carbohydrate-binding site. In this review literature data about structure and carbohydrate specificity of galectins are discussed. The role of galectins in the regulation of cell adhesion in immune response, inflammation, and cancer progression is considered.     

Role of galectins in inflammatory and immunomodulatory processes

Galectins are members of a highly conserved family of beta-galactoside-binding animal lectins. Presently, more than 14 members have been identified and additional homologues are likely to be discovered. Given their conservation throughout animal evolution, it is not surprising that they could play key roles in innate and adaptive immune responses, through sugar-dependent and -independent mechanisms. Recently, it has become increasingly clear that galectins can differentially affect cellular activation and function. These biological effects attracted attention of researchers in cell biology, biochemistry, glycobiology and immunology, not only in the mode of action of galectins, but also in their role as putative modulators of immune surveillance, apoptosis, cell adhesion and chemotaxis. Here we will summarize the state-of-the-art of the effects of galectins in inflammatory and immunomodulatory processes. In addition, we will discuss in-depth the current knowledge about the effects of this enigmatic family of animal lectins and their glycoligands in the progression, diagnosis and treatment of different pathological processes such as autoimmunity, allergy, infection and chronic inflammation.     

Vascular galectins: Regulators of tumor progression and targets for cancer therapy

Galectins are a family of carbohydrate binding proteins with a broad range of cytokine and growth factor-like functions in multiple steps of cancer progression. They contribute to tumor cell transformation, promote tumor angiogenesis, hamper the anti-tumor immune response, and facilitate tumor metastasis. Consequently, galectins are considered as multifunctional targets for cancer therapy. Interestingly, many of the functions related to tumor progression can be linked to galectins expressed by endothelial cells in the tumor vascular bed. Since the tumor vasculature is an easily accessible target for cancer therapy, understanding how galectins in the tumor endothelium influence cancer progression is important for the translational development of galectin-targeting therapies.     

The sweet and bitter sides of galectins in melanoma progression

Melanoma is the leading cause of skin cancer-related deaths, which is due in large part to its aggressive behavior, resistance to therapy, and ability to metastasize to multiple organs such as the lymph nodes, lung, and brain. Melanoma progresses in a stepwise manner from the benign nevus, to radial spreading through the dermis, to a vertical invasive phase, and finally to metastasis. The carbohydrate-binding family of galectins has a strong influence on each phase of melanoma progression through their effects on immune surveillance, angiogenesis, cell migration, tumor cell adhesion, and the cellular response to chemotherapy. Galectins share significant homology in their carbohydrate recognition domain (CRD), which mediates binding to an array of N-glycosylated proteins located on the surface of tumor cells, endothelial cells, T-cells, and to similarly glycosylated extracellular matrix proteins. Galectins are also present within tumor cells where they perform anti-apoptotic functions and enhance intracellular signaling that results in deregulated expression of genes involved in tumor progression. The most extensively studied galectins, galectin-1 and galectin-3, have been shown to have profound effects on melanoma growth and metastasis by influencing many of these biological processes.     

Galectins as modulators of receptor tyrosine kinases signaling in health and disease

Receptor tyrosine kinases (RTKs) constitute a large group of cell surface proteins that mediate communication of cells with extracellular environment. RTKs recognize external signals and transfer information to the cell interior, modulating key cellular activities, like metabolism, proliferation, motility, or death. To ensure balanced stream of signals the activity of RTKs is tightly regulated by numerous mechanisms, including receptor expression and degradation, ligand specificity and availability, engagement of co-receptors, cellular trafficking of the receptors or their post-translational modifications. One of the most widespread post-translational modifications of RTKs is glycosylation of their extracellular domains. The sugar chains attached to RTKs form a new layer of information, so called glyco-code that is read by galectins, carbohydrate binding proteins. Galectins are family of fifteen lectins implicated in immune response, inflammation, cell division, motility and death. The versatility of cellular activities attributed to galectins is a result of their high abundance and diversity of their cellular targets. A various sugar specificity of galectins and the differential ability of galectin family members to form oligomers affect the spatial distribution and the function of their cellular targets. Importantly, galectins and RTKs are tightly linked to the development, progression and metastasis of various cancers. A growing number of studies points on the close cooperation between RTKs and galectins in eliciting specific cellular responses. This review focuses on the identified complexes between galectins and RTK members and discusses their relevance for the cell physiology both in healthy tissues and in cancer.     

Galectins distinctively regulate central monocyte and macrophage function

Monocytes and macrophages link the innate and adaptive immune systems and protect the host from the outside world. In inflammatory disorders their activation leads to tissue damage. Galectins have emerged as central regulators of the immune system. However, if they regulate monocyte/macrophage physiology is still unknown.Binding of Gal-1, Gal-2, Gal-3 and Gal-4 to monocytes/macrophages, activation, cytokine secretion and apoptosis were determined by FACS, migration by Transwell system and phagocytosis by phagotest. Supernatants from macrophages co-cultured with galectins revealed their influence on T-cell function.In our study Gal-1, Gal-2, Gal-4, and partly Gal-3 bound to monocytes/macrophages. Galectins prevented Salmonella-induced MHCII upregulation. Cytokine release was distinctly induced by different galectins. T-cell activation was significantly restricted by supernatants of macrophages co-cultured in the presence of Gal-2 or Gal-4. Furthermore, all galectins tested significantly inhibited monocyte migration. Finally, we showed for the first time that galectins induce potently monocyte, but not macrophage apoptosis.Our study provides evidence that galectins distinctively modulate central monocyte/macrophage function. By inhibiting T-cell function via macrophage priming, we show that galectins link the innate and adaptive immune systems and provide new insights into the action of sugar-binding proteins.     

Galectins: an evolutionarily conserved family of animal lectins with multifunctional properties; a trip from the gene to clinical therapy.

Galectins constitute a family of evolutionarily conserved animal lectins, which are defined by their affinity for poly-N-acetyllactosamine-enriched glycoconjugates and sequence similarities in the carbohydrate recognition domain. During the past decade, attempts to dissect the functional role for galectins in vivo have been unsuccessful in comparison to the overwhelming information reached at the biochemical and molecular levels. The present review deals with the latest advances in galectin research and is aimed at validating the functional significance of these carbohydrate-binding proteins. Novel implications of galectins in cell adhesion, cell growth regulation, immunomodulation, apoptosis, inflammation, embryogenesis, metastasis and pre-mRNA splicing will be particularly discussed in a trip from the gene to the clinical therapy. Elucidation of the molecular mechanisms involved in galectin functions will certainly open new avenues not only in biomedical research, but also at the level of disease diagnosis and clinical intervention, attempting to delineate new therapeutic strategies in autoimmune diseases, inflammatory processes, allergic reactions and tumor spreading.     

Contribution of allergic inflammatory response to the pathogenesis of malaria disease

Plasmodium falciparum, the aetiological agent of human lethal malaria, is responsible for over 2 million deaths per year and malaria episodes may vary considerably in their severity and clinical manifestations. Dysregulated balance of the inflammatory response and a defect in the anti-Plasmodium parasite immune response represent the hallmarks of malaria disease. Among the many possible mechanisms, it is now widely recognized that the production of pro-inflammatory mediators and cytokines and upregulation of endothelial cell adhesion molecules play important roles in malaria pathogenesis. We and others provided evidence that some components of allergic inflammatory response to malaria parasites or elicited by by-products of parasite infection may contribute to malaria pathogenesis. This review provides some clue regarding these mechanisms where mast cells and histamine, an inflammatory mediator generated following IgE-independent or IgE-mediated immune response, were found to play a major role in parasite transmission and malaria pathogenesis, respectively. This article is part of a Special Issue entitled: Mast cells in inflammation.     

Shedding light on the immunomodulatory properties of galectins: novel regulators of innate and adaptive immune responses

Galectins are a large family of structurally related beta-galactoside-binding proteins that play a pivotal role in the control of cell differentiation, proliferation, activation and apoptosis of many different cell types including immune cells. By crosslinking specific glycoconjugates, different members of the galectin family behave as pro-inflammatory or anti-inflammatory "cytokine-like" mediators, acting at different levels of innate and adaptive immune responses. Here we will review recent advances on the role of galectins in key events of the immune and inflammatory response, such as tolerance induction, cell cycle progression, cell adhesion, chemotaxis, antigen presentation and apoptosis. In particular we will examine the influence of individual members of the galectin family in the physiology of different immune cell types involved in innate and adaptive immune responses. Moreover, we will discuss the importance of these sugar-binding proteins as therapeutic targets in Th1- and Th2-mediated immune disorders, an exciting area for future research.     

cDNA cloning and mRNA expression of a tandem-repeat galectin (PoGal2) from the pearl oyster, Pinctada fucata

Galectins can recognize and specifically bind to β-galactoside residues, playing crucial roles in innate immune responses of vertebrates and invertebrates. We cloned the cDNA of a tandem-repeat galectin from the pearl oyster Pinctada fucata (designated as PoGal2). PoGal2 cDNA is 1347 bp long and consists of a 5'-untranslated region (UTR) of 3 bp, a 3'-UTR of 297 bp with one cytokine RNA instability motif (ATTTA), and an open reading frame of 1047 bp, encoding a polypeptide of 349 amino acids, with an estimated molecular mass of 38.1 kDa and a theoretical isoelectric point of 8.5. PoGal2 contains two carbohydrate recognition domains (CRDs); both have the conserved carbohydrate-binding motifs H-NPR and WG-EE. PoGal2 shares 50.6 and 50.9% identity with those of abalone (Haliotis discus) and the Manila clam (Venerupis philippinarum), respectively. Phylogenetic analysis revealed that the tandem-repeat galectins formed two clades for the different species. Molluscan tandem-repeat galectins were clustered into a single clade, and nematode tandem-repeat galectins were clustered into another single clade. In both clades, CRD-N and CRD-C were divided into different groups. PoGal2 mRNA was constitutively expressed in all tissues analyzed, and the expression level of PoGal2 mRNA was found to be significantly up-regulated in digestive glands, gills and hemocytes after Vibrio alginolyticus stimulation/infection. Expression profile analysis showed that the expression level of PoGal2 mRNA was significantly up-regulated at 8, 12 and 24 h after V. alginolyticus infection. These results suggest that PoGal2 is a constitutive and inducible acute-phase protein involved in the innate immune response of pearl oysters.     

Toxoplasma gondii Infection Induces Suppression in a Mouse Model of Allergic Airway Inflammation

Allergic asthma is an inflammatory disorder characterized by infiltration of the airway wall with inflammatory cells driven mostly by activation of Th2-lymphocytes, eosinophils and mast cells. There is a link between increased allergy and a reduction of some infections in Western countries. Epidemiological data also show that respiratory allergy is less frequent in people exposed to orofecal and foodborne microbes such as Toxoplasma gondii. We previously showed that both acute and chronic parasite T. gondii infection substantially blocked development of airway inflammation in adult BALB/c mice. Based on the high levels of IFN-γ along with the reduction of Th2 phenotype, we hypothesized that the protective effect might be related to the strong Th1 immune response elicited against the parasite. However, other mechanisms could also be implicated. The possibility that regulatory T cells inhibit allergic diseases has received growing support from both animal and human studies. Here we investigated the cellular mechanisms involved in T. gondii induced protection against allergy. Our results show for the first time that thoracic lymph node cells from mice sensitized during chronic T. gondii infection have suppressor activity. Suppression was detected both in vitro, on allergen specific T cell proliferation and in vivo, on allergic lung inflammation after adoptive transference from infected/sensitized mice to previously sensitized animals. This ability was found to be contact- independent and correlated with high levels of TGF-β and CD4(+)FoxP3(+) cells.     

Shedding light on the immunomodulatory properties of galectins: Novel regulators of innate and adaptive immune responses

Galectins are a large family of structurally related β-galactoside-binding proteins that play a pivotal role in the control of cell differentiation, proliferation, activation and apoptosis of many different cell types including immune cells. By crosslinking specific glycoconjugates, different members of the galectin family behave as pro-inflammatory or anti-inflammatory “cytokine-like” mediators, acting at different levels of innate and adaptive immune responses. Here we will review recent advances on the role of galectins in key events of the immune and inflammatory response, such as tolerance induction, cell cycle progression, cell adhesion, chemotaxis, antigen presentation and apoptosis. In particular we will examine the influence of individual members of the galectin family in the physiology of different immune cell types involved in innate and adaptive immune responses. Moreover, we will discuss the importance of these sugar-binding proteins as therapeutic targets in Th1- and Th2-mediated immune disorders, an exciting area for future research. Published in 2004.     

Galactose specific lectins from prostate tissue with different pathologies: biochemical and cellular studies

Background

Galectins—galactose-specific lectins are involved in various types of cell activities, including apoptosis, cell cycle regulation, inflammation and cell transformation. Galectins are implicated in prostate malignat transformation. It is not known yet if prostate glands with different grade of pathologies are expressing different galectins and if these galectins express different effects on the cell viability.

Methods

Cytosolic galactose-spesific lectin fractions from prostate tissue with different diagnosis were purified by affinity chromatography and analyzed by electrophoresis in polyacrylamide gel electrophoresis with sodium dodecyl sulphate. The lectin effects in a source-dependent maner were studied on cell viability on peripheral lymphocytes by MTT reduction method and on apoptosis by flow cytometry method.

Results

Affinity purified galactose-specific lectins fractions from normal and pathological tissue samples are characterized with different protein composition and they express different effects on cell viability and apoptosis.

Conclusion

The effects of cytosolic galactose-specific lectins depend on the source of lectin fraction (glandular tissue disease). We suppose that the released cytosolic galectins from prostatic high grade intraepithelial neoplasia and adenocarcinoma tissue could suppress the immune status of the host patients.

     

Galectin-3: its role in asthma and potential as an anti-inflammatory target

Galectins constitute an evolutionary conserved family that bind to β-galactosides. Increasing evidence shows that galectins are involved in many fundamental biological processes such as cellular communication, inflammation, differentiation and apoptosis. Changes in galectin-3 (Gal-3) expression are commonly seen in cancer and pre-cancerous conditions, and Gal-3 may be involved in the regulation of diverse cancer cell activities that contribute to tumourigenesis, cancer progression and metastasis. In addition, Gal-3 is a pro-inflammatory regulator in rheumatoid arthritis. Gal-3 has been shown to be involved in many aspects in allergic inflammation, such as eosinophil recruitment, airway remodeling, development of a Th2 phenotype as well as increased expression of inflammatory mediators. In an in vivo model it was shown that bronchoalveolar lavage (BAL) fluid from ovalbumin-challenged mice contained significantly higher levels of Gal-3 compared to control mice. The molecular mechanisms of Gal-3 in human asthma have not been fully elucidated. This review will focus on what is known about the Gal-3 and its role in the pathophysiological mechanisms of asthma to evaluate the potential of Gal-3 as a biomarker and therapeutic target of asthma.     

Emerging role of alpha2,6-sialic acid as a negative regulator of galectin binding and function

Galectins are β-galactoside-binding lectins that regulate diverse cell behaviors, including adhesion, migration, proliferation, and apoptosis. Galectins can be expressed both intracellularly and extracellularly, and extracellular galectins mediate their effects by associating with cell-surface oligosaccharides. Despite intensive current interest in galectins, strikingly few studies have focused on a key enzyme that acts to inhibit galectin signaling, namely β-galactoside α2,6-sialyltransferase (ST6Gal-I). ST6Gal-I adds an α2,6-linked sialic acid to the terminal galactose of N-linked glycans, and this modification blocks galectin binding to β-galactosides. This minireview summarizes the evidence suggesting that ST6Gal-I activity serves as an "off switch" for galectin function.     

Cutting edge: T cell Ig mucin-3 reduces inflammatory heart disease by increasing CTLA-4 during innate immunity

Autoimmune diseases can be reduced or even prevented if proinflammatory immune responses are appropriately down-regulated. Receptors (such as CTLA-4), cytokines (such as TGF-beta), and specialized cells (such as CD4+CD25+ T regulatory cells) work together to keep immune responses in check. T cell Ig mucin (Tim) family proteins are key regulators of inflammation, providing an inhibitory signal that dampens proinflammatory responses and thereby reducing autoimmune and allergic responses. We show in this study that reducing Tim-3 signaling during the innate immune response to viral infection in BALB/c mice reduces CD80 costimulatory molecule expression on mast cells and macrophages and reduces innate CTLA-4 levels in CD4+ T cells, resulting in decreased T regulatory cell populations and increased inflammatory heart disease. These results indicate that regulation of inflammation in the heart begins during innate immunity and that Tim-3 signaling on cells of the innate immune system critically influences regulation of the adaptive immune response.     

IL-5-induced hypereosinophilia suppresses the antigen-induced immune response via a TGF-beta-dependent mechanism

Although eosinophils play an essential role in allergic inflammation, their role has recently been under controversy. Epidemic studies suggest that hypereosinophilia induced by parasite infection could suppress subsequent Ag sensitization, although the mechanism has not been fully clarified. In this study, we investigated whether eosinophils could suppress the Ag-specific immune response in the airway. BALB/c mice were sensitized and airway challenged with OVA. Systemic hypereosinophilia was induced by delivery of an IL-5-producing plasmid. IL-5 gene delivery suppressed the Ag-specific proliferation and cytokine production of CD4+ T cells in the spleen. IL-5 gene delivery before OVA sensitization significantly suppressed airway eosinophilia and hyperresponsiveness provoked by subsequent OVA airway challenge, while delivery during the OVA challenge did not suppress them. This IL-5-induced immune suppression was abolished in eosinophil-ablated mice, suggesting an essential role of eosinophils. IL-5 treatment increased the production of TGF-beta1 in the spleen, and we demonstrated that the main cellular source of TGF-beta1 production was eosinophils, using eosinophil-ablated mice and depletion study. TGF-beta1, but not IL-5 itself, suppressed the Ag-specific immune response of CD4+ T cells in vitro. Furthermore, IL-5 treatment enhanced phosphorylation of Smad2 in CD4+ T cells. Finally, a TGF-beta type I receptor kinase inhibitor restored this IL-5-induced immune suppression both in vitro and in vivo. These results suggest that IL-5-induced hypereosinophilia could suppress sensitization to Ag via a TGF-beta-dependent mechanism, thus suppressed allergic airway inflammation. Therefore, hypereosinophilia could reveal an immunosuppressive effect in the early stage of Ag-induced immune response.     

Allergic airway inflammation inhibits pulmonary antibacterial host defense

The innate immune system of the lung is a multicomponent host defense system and in addition has an instructing role in regulating the quality and quantity of the adaptive immune response. When the interaction between innate and adaptive immunity is disturbed, pathological conditions such as asthma can develop. It was the aim of the study to investigate the effect of the allergic inflammation of the lung on the innate host defense during bacterial infection. Human bronchial epithelial cells were preincubated with Th2 cytokines and infected with Pseudomonas aeruginosa. The effect of the Th2 cytokines on the mRNA levels of antimicrobial peptides and the antimicrobial activity of HBEC was determined. To investigate the influence of an allergic inflammation on pulmonary host defense in vivo, mice sensitized and challenged with OVA were infected with P. aeruginosa, and the number of viable bacteria in the lungs was determined together with markers of inflammation like cytokines and antimicrobial peptides. Exposure of airway epithelial cells to Th2 cytokines resulted in a significantly decreased antimicrobial activity of the cells and in suppressed mRNA levels of the antimicrobial peptide human beta-defensin 2. Furthermore, mice with allergic airway inflammation had significantly more viable bacteria in their lungs after infection. This was consistent with reduced levels of proinflammatory cytokines and of the antimicrobial peptide cathelin-related antimicrobial peptide. These results show that an allergic airway inflammation suppresses the innate antimicrobial host defense. The adaptive immune system modulates the functions of the pulmonary innate immune system.     

The roles of autotaxin/lysophosphatidic acid in immune regulation and asthma

Lysophosphatidic acid (LPA) species are present in almost all organ systems and play diverse roles through its receptors. Asthma is an airway disease characterized by chronic allergic inflammation where various innate and adaptive immune cells participate in establishing Th2 immune response. Here, we will review the contribution of LPA and its receptors to the functions of immune cells that play a key role in establishing allergic airway inflammation and aggravation of allergic asthma.