Absence Of Galectin-3 Research Articles

Galectin-3 interferes with tissue repair and promotes cardiac dysfunction and comorbidities in a genetic heart failure model.

Galectin-3, a biomarker for heart failure (HF), has been associated with myocardial fibrosis. However, its causal involvement in HF pathogenesis has been questioned in certain models of cardiac injury-induced HF. To address this, we used desmin-deficient mice (des-/-), a model of progressive HF characterized by cardiomyocyte death, spontaneous inflammatory responses sustaining fibrosis, and galectin-3 overexpression. Genetic ablation or pharmacological inhibition of galectin-3 led to improvement of cardiac function and adverse remodeling features including fibrosis. Over the course of development of des-/- cardiomyopathy, monitored for a period of 12months, galectin-3 deficiency specifically ameliorated the decline in systolic function accompanying the acute inflammatory phase (4-week-old mice), whereas a more pronounced protective effect was observed in older mice, including the preservation of diastolic function. Interestingly, the cardiac repair activities during the early inflammatory phase were restored under galectin-3 deficiency by increasing the proliferation potential and decreasing apoptosis of fibroblasts, while galectin-3 absence modulated macrophage-fibroblast coupled functions and suppressed both pro-fibrotic activation of cardiac fibroblasts and pro-fibrotic gene expression in the des-/- heart. In addition, galectin-3 also affected the emphysema-like comorbid pathology observed in the des-/- mice, as its absence partially normalized lung compliance. Collectively galectin-3 was found to be causally involved incardiac adverse remodeling, inflammation, and failure by affecting functions of cardiac fibroblasts and macrophages. In concordance with this role, the effectiveness of pharmacological inhibition in ameliorating cardiac pathology features establishes galectin-3 as a valid intervention target for HF, with additive benefits for treatment of associated comorbidities, such as pulmonary defects. Schematic illustrating top to bottom, the detrimental role of galectin-3 (Gal3)in heart failure progression: desmin deficiency-associated spontaneous myocardial inflammation accompanying cardiac cell death (reddish dashed border) is characterized by infiltration of macrophages (round cells) and up-regulation of Lgals3 (encoding secretablegalectin-3, green) and detrimental macrophage-related genes (Ccr2 and Arg1). In this galectin-3-enriched milieu, the early up-regulation of profibrotic gene expression (Tgfb1, Acta2, Col1a1), in parallel to the suppression of proliferative activities and a potential of senescence induction by cardiac fibroblasts (spindle-like cells), collectively promote des-/- cardiac fibrosis and dysfunction establishing heart failure (left panel). Additionally, galectin-3+ macrophage-enrichment accompanies the development of emphysema-like lung comorbidities. In the absence of galectin-3 (right panel), the effect of macrophage-fibroblast dipole and associated events are modulated (grey color depicts reduced expression or activities) leading to attenuated cardiac pathology in the des-/-Lgals3-/- mice. Pulmonary comorbidities are also limited.

Altered expression of genes related to innate antifungal immunity in the absence of galectin-3

ABSTRACT Galectin-3 (Gal-3) is the most studied member of the animal galectin family, which comprises β-galactoside-binding lectins and participates in several cellular events. Its expression in cells involved in innate and adaptive immunity is related to anti- and proinflammatory functions, signaling an important role in inflammatory, infectious, and tumorigenesis processes. Mice deficient in Gal-3 exhibit important phenotypes, but it is unclear whether these phenotypes reflect an impairment of the functions of this protein. Gal-3 plays an important role in modulating the immune response to different pathogenic microorganisms. However, the role of Gal-3 in immunity to infection is still poorly understood. Therefore, we investigated the effects of Gal-3 deletion on the expression of genes involved in the innate immune response in the lungs, spleens, and brains of Gal-3 KO mice. Gene profiling expression analysis suggested that Gal-3 deletion resulted in differentially modulated expression of the genes encoding beta-glucan, mannose and chitin-responsive pattern recognition receptors, signal transduction, inflammation, and phagocytosis. Our data thus suggest the importance of Gal-3 expression in the host innate immune system.

Interaction between galectin-3 and cystinosin uncovers a pathogenic role of inflammation in kidney involvement of cystinosis

Inflammation is involved in the pathogenesis of many disorders. However, the underlying mechanisms are often unknown. Here, we test whether cystinosin, the protein involved in cystinosis, is a critical regulator of galectin-3, a member of the β-galactosidase binding protein family, during inflammation. Cystinosis is a lysosomal storage disorder and, despite ubiquitous expression of cystinosin, the kidney is the primary organ impacted by the disease. Cystinosin was found to enhance lysosomal localization and degradation of galectin-3. In Ctns-/- mice, a mouse model of cystinosis, galectin-3 is overexpressed in the kidney. The absence of galectin-3 in cystinotic mice ameliorates pathologic renal function and structure and decreases macrophage/monocyte infiltration in the kidney of the Ctns-/-Gal3-/- mice compared to Ctns-/- mice. These data strongly suggest that galectin-3 mediates inflammation involved in kidney disease progression in cystinosis. Furthermore, galectin-3 was found to interact with the pro-inflammatory cytokine Monocyte Chemoattractant Protein-1, which stimulates the recruitment of monocytes/macrophages, and proved to be significantly increased in the serum of Ctns-/- mice and also patients with cystinosis. Thus, our findings highlight a new role for cystinosin and galectin-3 interaction in inflammation and provide an additional mechanistic explanation for the kidney disease of cystinosis. This may lead to the identification of new drug targets to delay cystinosis progression.

Galectin-3 supports stemness in ovarian cancer stem cells by activation of the Notch1 intracellular domain.

Ovarian cancer is the most lethal gynecologic disease because usually, it is lately sensed, easily acquires chemoresistance, and has a high recurrence rate. Recent studies suggest that ovarian cancer stem cells (CSCs) are involved in these malignancies. Here, we demonstrated that galectin-3 maintains ovarian CSCs by activating the Notch1 intracellular domain (NICD1). The number and size of ovarian CSCs decreased in the absence of galectin-3, and overexpression of galectin-3 increased them. Overexpression of galectin-3 increased the resistance for cisplatin and paclitaxel-induced cell death. Silencing of galectin-3 decreased the migration and invasion of ovarian cancer cells, and overexpression of galectin-3 reversed these effects. The Notch signaling pathway was strongly activated by galectin-3 overexpression in A2780 cells. Silencing of galectin-3 reduced the levels of cleaved NICD1 and expression of the Notch target genes, Hes1 and Hey1. Overexpression of galectin-3 induced NICD1 cleavage and increased expression of Hes1 and Hey1. Moreover, overexpression of galectin-3 increased the nuclear translocation of NICD1. Interestingly, the carbohydrate recognition domain of galectin-3 interacted with NICD1. Overexpression of galectin-3 increased tumor burden in A2780 ovarian cancer xenografted mice. Increased expression of galectin-3 was detected in advanced stages, compared to stage 1 or 2 in ovarian cancer patients, suggesting that galectin-3 supports stemness of these cells. Based on these results, we suggest that targeting galectin-3 may be a potent approach for improving ovarian cancer therapy.

The deficiency of galectin-3 in stromal cells leads to enhanced tumor growth and bone marrow metastasis.

BackgroundGalectin-3 is a multifunctional β-galactoside-binding lectin that once synthesized, is expressed in the nucleus, cytoplasm, cell surface and in the extracellular environment. Because of its unique structure, galectin-3 can oligomerize forming lattice upon binding to multivalent oligossacharides and influence several pathologic events such as tumorigenesis, invasion and metastasis.MethodsIn our study, balb/c Lgals3+/+ and Lgals3−/− female mice were inoculated in the fourth mammary fat pad with 4T1 breast cancer cell line. The primary tumor, inguinal lymph nodes and iliac bone marrow were evaluated 15, 21 and 28 days post-injection. The primary tumor growth was evaluated by measuring the external diameter, internal growth by ultrasound and weight of the excised tumor. The presence of cancer cells in the draining lymph nodes and iliac crest bone marrow were performed by immunohistochemistry, PCR and clonogenic metastatic assay.ResultsIn this study we demonstrated that the deletion of galectin-3 in the host affected drastically the in vivo growth rate of 4T1 tumors. The primary tumors in Lgals3−/− mice displayed a higher proliferative rate (p < 0,05), an increased necrotic area (p < 0,01) and new blood vessels with a wider lumen in comparison with tumors from Lgals3+/+ mice (P < 0,05). Moreover, we detected a higher number of 4T1-derived metastatic colonies in the lymph nodes and the bone marrow of Lgals3−/− mice (p < 0,05). Additionally, healthy Lgals3−/− control mice presented an altered spatial distribution of CXCL12 in the bone marrow, which may explain at least in part the initial colonization of this organ in Lgals3−/− injected with 4T1 cells.ConclusionsTaken together, our results demonstrate for the first time that the absence of galectin-3 in the host microenvironment favors the growth of the primary tumors, the metastatic spread to the inguinal lymph nodes and bone marrow colonization by metastatic 4T1 tumor cells.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2679-1) contains supplementary material, which is available to authorized users.

Differential development of oil granulomas induced by pristane injection in galectin-3 deficient mice.

BackgroundGalectin-3 is known to be a lectin that plays an important role in inflammatory processes, acting as pro-inflammatory mediator in activation and migration of neutrophils and macrophages, as well as in the phagocytic function of these cells. The injection of mineral oils into the peritoneal cavity of mice, such as 2, 6, 10, 14-tetramethylpentadecane (pristane), induce a chronic granulomatous inflammatory reaction which is rich in macrophages, B cells and peritoneal plasma cells known as oil granuloma. In addition, this inflammatory microenvironment provided by oil granulomas is also an important site of plasmacytoma induction, which are dependent on cytokine production and cellular mobilization.Here, we have analyzed the role of galectin-3 in inflammatory cells mobilization and organization after pristane injection characterizing granulomatous reaction through the formation of oil granulomas.ResultsIn galectin-3 deficient mice (gal-3−/−), the mobilization of inflammatory cells, between peritoneal cavity and bone marrow, was responsible for the formation of disorganized oil granulomas, which presented scattered cells, large necrotic areas and low amounts of extracellular matrix. The production of inflammatory cytokines partially explained the distribution of cells through peritoneal cavity, since high levels of IL-6 in gal-3−/− mice led to drastically reduction of B1 cells. The previous pro-inflammatory status of these animals also explains the excess of cell death and disruption of oil granulomas architecture.ConclusionsOur data indicate, for the first time, that the disruption in the inflammatory cells migration in the absence of galectin-3 is a crucial event in the formation and organization of oil granulomas.Electronic supplementary materialThe online version of this article (doi:10.1186/s12865-015-0133-9) contains supplementary material, which is available to authorized users.

Lack of galectin-3 up-regulates IgA expression by peritoneal B1 lymphocytes during B cell differentiation.

Galectin-3 is a β-galactoside-binding protein with an inhibitory role in B cell differentiation into plasma cells in distinct lymphoid tissues. We use a model of chronic schistosomiasis, a well-characterized experimental disease hallmarked by polyclonal B cell activation, in order to investigate the role of galectin-3 in controlling IgA production through peritoneal B1 cells. Chronically infected, galectin-3-deficient mice (Lgals3(-/-)) display peritoneal fluid hypercellularity, increased numbers of atypical peritoneal IgM(+)/IgA(+) B1a and B1b lymphocytes and histological disturbances in plasma cell niches when compared with Lgals3(+/+) mice. Similar to our infection model, peritoneal B1 cells from uninfected Lgals3(-/-) mice show enhanced switching to IgA after in vitro treatment with interleukin-5 plus transforming growth factor-β (IL-5 + TGF-β1). A higher number of IgA(+) B1a lymphocytes was found in the peritoneal cavity of Lgals3(-/-)-uninfected mice at 1 week after i.p. injection of IL-5 + TGF-β1; this correlates with the increased levels of secreted IgA detected in the peritoneal fluid of these mice after cytokine treatment. Interestingly, a higher number of degranulated mast cells is present in the peritoneal cavity of uninfected and Schistosoma mansoni-infected Lgals3(-/-) mice, indicating that, at least in part, mast cells account for the enhanced differentiation of B1 into IgA-producing B cells found in the absence of galectin-3. Thus, a novel role is revealed for galectin-3 in controlling the expression of surface IgA by peritoneal B1 lymphocytes; this might have important implications for manipulating the mucosal immune response.

Characterization of LGALS3 (galectin-3) as a player in DNA damage response

DNA damage repair (DDR) is an orchestrated process encompassing the injury detection to its complete resolution. DNA double-strand break lesions are repaired mainly by two distinct mechanisms: the error-free homologous recombination (HR) and the error-prone non-homologous end-joining. Galectin-3 (GAL3) is the unique member of the chimeric galectins subfamily and is reported to be involved in several cancer development and progression related events. Recently our group described a putative protein interaction between GAL3 and BARD1, the main partner of breast and ovarian cancer susceptibility gene product BRCA1, both involved in HR pathway. In this report we characterized GAL3/BARD1 protein interaction and evaluated the role of GAL3 in DDR pathways using GAL3 silenced human cells exposed to different DNA damage agents. In the absence of GAL3 we observed a delayed DDR response activation, as well as a decrease in the G2/M cell cycle checkpoint arrest associated with HR pathway. Moreover, using a TAP-MS approach we also determined the protein interaction network of GAL3.

Tumors as complex organs: are cancers manageable through the modification of their microenvironment?

Cancers behave as organoids, composed not only by genetically altered tumor cells, but also by a variety of non-tumoral cells, such as fibroblasts, macrophages and endothelial cells among others. Cellular interactions within this organoid dictate the rate of tumor progression, and therefore the accumulation of heterogeneous genotypes which characterize the tumor mass at the moment of diagnosis. Evidence for both homotypic and heterotypic cooperation between cells within the tumor microenvironment exist. We will show evidence for fluctuations in the expression of a specific tumor marker, namely galectin-3. Galectin-3 is an animal lectin that is found in diverse cellular compartments, depending on the cellular context and functional state of cells. Normal cells tend to accumulate galectin-3 in the nucleus. Upon malignant transformation, galectin-3 may concentrate in the cytoplasm and can be secreted to the extracellular matrix, where it acts as a matricellular protein, interfering with integrin function among other cell surface glycoproteins. We had shown a focal accumulation of galectin-3 in glioblastomas. Galectin-3 expression was associated to a very specific tumor microenvironment, the pseudopalisades- areas of viable tumor cells surrounding necrotic areas that are commonly found in advanced stages of glioblastomas. Galectin-3 expression in hypoxic and nutrient deprived cells is associated the activation of HIF-1a and it was inhibitable by NF-kB antagonists. In glioblastoma cells, galectin-3 expression was associated with its translocation to mitochondria, suggesting its involvement in mitochondrial homeostasis. Inhibition of galectin-3 expression led to increased cell death, indicating that galectin-3 acts as a prosurvival factor in very specific tumor microenvironments associated with glioblastoma progression. The protumoral role of galectin-3 was also observed in murine melanomas, engrafted in both wild type and galectin-3-deficient mice. Absence of galectin-3 from both tumoral and stromal compartments was associated with attenuated tumor growth, as compared to an experimental condition where both tumor and stromal cells expressed galectin-3. Intriguingly, de novo expression of galectin-3 was frequently observed in tumors derived from cells that did not express galectin-3 when these cells were engrafted in galectin-3 deficient mice. This observation prompted us to investigate whether galectin-3 expressing cells would favor tumor growth when admixed with galectin-3 negative cells. Indeed, when cells are admixed, tumors grew much more efficiently than those engraftments of either cell alone, indicating cooperation between galectin-3 expressing cells and galectin-3 negative cells. Further experiments indicated that galectin-3 expression is related with the induction of a proangiogenic tumor environment. Thus, targeting galectin-3 expression in selected tumors may prove to be an effective strategy to control tumor growth. Angiogenesis and vasculature function are critically altered in cancers, which are usually ill-perfused. Evidence for activation of both angiotensin and bradykinin-dependent pathways within the tumor microenvironment of melanomas will be discussed. Blockage of vasoactive peptide-dependent pathways may control tumor angiogenesis and therefore may control tumor growth. Indeed, epidemiological studies are now indicating that individuals receiving specific blockers of angiotensin receptors may be relatively protected from the development of tumors. In a clinical setting, however, antiangiogenic drugs would be preferably used in combination with chemotherapeutic drugs. Vasculature function, however is also critical for the proper delivery of chemotherapeutic drugs to tumors, specific therapeutic windows for the application of antiangiogenic drugs need to be identified. This notion will be further discussed. Altogether, the examples above call for a necessary understanding of tumor physiology, which seems to be under appreciated in the design of experimental/clinical trials.

Galectin‐3 deficiency protects pancreatic islet cells from cytokine‐triggered apoptosis in vitro

Beta cell apoptosis is a hallmark of diabetes. Since we have previously shown that galectin-3 deficient (LGALS3(-/-) ) mice are relatively resistant to diabetes induction, the aim of this study was to examine whether beta cell apoptosis depends on the presence of galectin-3 and to delineate the underlying mechanism. Deficiency of galectin-3, either hereditary or induced through application of chemical inhibitors, β-lactose or TD139, supported survival and function of islet beta cells compromised by TNF-α + IFN-γ + IL-1β stimulus. Similarly, inhibition of galectin-3 by β-lactose or TD139 reduced cytokine-triggered apoptosis of beta cells, leading to conclusion that endogenous galectin-3 propagates beta apoptosis in the presence of an inflammatory milieu. Exploring apoptosis-related molecules expression in primary islet cells before and after treatment with cytokines we found that galectin-3 ablation affected the expression of major components of mitochondrial apoptotic pathway, such as BAX, caspase-9, Apaf, SMAC, caspase-3, and AIF. In contrast, anti-apoptotic molecules Bcl-2 and Bcl-XL were up-regulated in LGALS3(-/-) islet cells when compared to wild-type (WT) counterparts (C57BL/6), resulting in increased ratio of anti-apoptotic versus pro-apoptotic molecules. However, Fas-triggered apoptotic pathway as well as extracellular signal-regulated kinase 1/2 (ERK1/2) was not influenced by LGALS-3 deletion. All together, these results point to an important role of endogenous galectin-3 in beta cell apoptosis in the inflammatory milieu that occurs during diabetes pathogenesis and implicates impairment of mitochondrial apoptotic pathway as a key event in protection from beta cell apoptosis in the absence of galectin-3.

Local and systemic effects of chronic peritonitis induced by pristane in the absence of galectin-3

Event Abstract Back to Event Local and systemic effects of chronic peritonitis induced by pristane in the absence of galectin-3 Camila Brand1*, Felipe L. Oliveira1, Thayse P. Costa1, Filipe E. Abreu1, Radovan Borojevic1, Roger Chammas2 and Márcia C. El-Cheikh1 1 Universidade Federal do Rio de Janeiro, Brazil 2 Universidade de São Paulo, Brazil Recent studies of our group show that galectin-3-/- (gal-3-/-) animals present larger amount of plasma cells in lymphoid organs. Furthermore, in B cell neoplasms, high concentrations of gal-3 provide greater tumor resistance and progression. An important model for induction of plasmacytomas is the injection of pristane, leading to chronic granulomatous inflammation rich in macrophages, plasma cells and peritoneal B cells. Thus, the objectives of this study were to evaluate quantitative and qualitatively peritoneal cavity and lymphoid organs, and analyze formation of oil granulomas due to stimulus of pristane. Animals were intraperitoneally injected with pristane or maintained under physiological conditions. We observed a significant increase of total cell number in peritoneal cavity of injected WT animals, in contrast to reduced cellularity of gal-3-/- animals. Kinetics of cell cycle from peritoneal cavity cells was modified and annexin-V+ cells were increased in gal-3-/- animals. Quantification of peritoneal subpopulations showed an increase in neutrophils, and decreased numbers of both B and T lymphocytes. The spleen presented large amounts of lipid droplets and CD138+ plasma cells abnormally distributed in gal-3-/- animals, forming cell clusters in splenic parenchyma. Tertiary lymphoid organs were formed in both groups, but in gal-3-/- mice less or none lymphoid structures were present in oil granulomas and annexin-V+ cells were increased compared to WT animal. The results obtained allow us to conclude that the kinetics of inflammatory cells occurs differently in the absence of galectin-3, modulating lymphoid and myeloid populations, both in peripheral regions, as peritoneal cavity, spleen and oil granulomas. Keywords: galectin-3, pristane, Peritoneal Cavity, oil granuloma, Lymphoid organs Conference: 15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013. Presentation Type: Abstract Topic: Immune receptors and signaling Citation: Brand C, Oliveira FL, Costa TP, Abreu FE, Borojevic R, Chammas R and El-Cheikh MC (2013). Local and systemic effects of chronic peritonitis induced by pristane in the absence of galectin-3. Front. Immunol. Conference Abstract: 15th International Congress of Immunology (ICI). doi: 10.3389/conf.fimmu.2013.02.00204 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 14 Mar 2013; Published Online: 22 Aug 2013. * Correspondence: Mrs. Camila Brand, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil, camilabrandc@gmail.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Camila Brand Felipe L Oliveira Thayse P Costa Filipe E Abreu Radovan Borojevic Roger Chammas Márcia C El-Cheikh Google Camila Brand Felipe L Oliveira Thayse P Costa Filipe E Abreu Radovan Borojevic Roger Chammas Márcia C El-Cheikh Google Scholar Camila Brand Felipe L Oliveira Thayse P Costa Filipe E Abreu Radovan Borojevic Roger Chammas Márcia C El-Cheikh PubMed Camila Brand Felipe L Oliveira Thayse P Costa Filipe E Abreu Radovan Borojevic Roger Chammas Márcia C El-Cheikh Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

In vivo function of galectin-3 in motile cilia of airway epithelium

Galectins, a family of beta-galactoside binding lectins, participate in an exceptionally broad range of biological processes. It has been established that galectin-3 localizes at the primary cilium in epithelial cells, and that the absence of galectin-3 leads to major growth defects in primary cilia. We have now extended these original observations by studying the consequences of galectin-3 null mutation on the biogenesis and function of motile cilia in vivo. Using confocal and electron microscopy, we show that endogenous galectin-3 is also located in the motile cilia of adult mouse tracheas. Ultrastructural studies reveal that the absence of galectin-3 leads to a large panel of cilium abnormalities, including swollen cilia, compound cilia, and also abnormal axonemal organization (deviations from the expected 9+2 microtubular organization). We also monitored ciliary beat patterns by high speed videomicroscopy. These experiments revealed that, although beating frequency is unchanged, the amplitude of the movement was drastically reduced in gal3-/tracheas. By following the dynamics of fluorescent beads applied to tracheal explants, we could demonstrate that the coordinated movement of the beads was severely affected in gal3-/tracheas, in comparison to wt tracheas. Collectively, these data establish that galectin-3 is required for correct biogenesis and function of motile cilia in adult mice. Despite these defects, gal3 mutant mice seem healthy in SPF animal house conditions. However, histological analyses and scanning electron microscopy revealed aberrant accumulation of mucus layers inside gal3-/tracheas, suggesting the mice suffer from insufficient mucociliary clearance.

Activated Wnt signaling pathway is not influenced by absence of galectin-3 in mice during tongue malignant transformation

Activated Wnt signaling pathway is not influenced by absence of galectin-3 in mice during tongue malignant transformation

The involvement of the spleen during chronic phase of Schistosoma mansoni infection in galectin-3-/- mice.

Schistosoma mansoni synthesizes glycoconjugates which interact with galectin-3, eliciting an intense humoral immune response. Moreover, it was demonstrated that galectin-3 regulates B cell differentiation into plasma cells. Splenomegaly is a hallmark event characterized by polyclonal B cell activation and enhancement of antibody production. Here, we investigated whether galectin-3 interferes with spleen organization and B cell compartment during chronic schistosomiasis, using wild type (WT) and galectin-3-/- mice. In chronically-infected galectin-3-/- mice the histological architecture of the spleen, including white and red pulps, was disturbed with heterogeneous lymphoid follicles, an increased number of plasma cells (CD19-B220-/lowCD138+) and a reduced number of macrophages (CD19-B220-Mac-1+CD138-) and B lymphocytes (CD19+B220+/highCD138-), compared with the WT infected mice. In the absence of galectin-3 there was an increase of annexin-V+PI- cells and a major presence of apoptotic cells in spleen compared with WT infected mice. In spleen of WT infected mice galectin-3 was largely expressed in lymphoid follicles and extrafollicular sites. Thus, we propose that galectin-3 plays a role in splenic architecture, controlling distinct events such as apoptosis, macrophage activity, B cell differentiation and plasmacytogenesis in the course of S. mansoni infection.

The bone marrow compartment is modified in the absence of galectin-3

Galectin-3 (gal-3) is a β-galactoside binding protein present in multivalent complexes with an extracellular matrix and with cell surface glycoconjugates. In this context, it can deliver a variety of intracellular signals to modulate cell activation, differentiation and survival. In the hematopoietic system, it was demonstrated that gal-3 is expressed in myeloid cells and surrounding stromal cells. Furthermore, exogenous and surface gal-3 drive the proliferation of myeloblasts in a granulocyte–macrophage colony-stimulating factor (GM-CSF)-dependent manner. Here, we investigated whether gal-3 regulates the formation of myeloid bone marrow compartments by studying galectin-3−/− mice (gal-3−/−) in the C57BL/6 background. The bone marrow histology of gal-3−/− mice was significantly modified and the myeloid compartments drastically disturbed, in comparison with wild-type (WT) animals. In the absence of gal-3, we found reduced cell density and diaphyseal disorders containing increased trabecular projections into the marrow cavity. Moreover, myeloid cells presented limited capacity to differentiate into mature myeloid cell populations in gal-3−/− mice and the number of hematopoietic multipotent progenitors was increased relative to WT animals. In addition, bone marrow stromal cells of these mice had reduced levels of GM-CSF gene expression. Taken together, our data suggest that gal-3 interferes with hematopoiesis, controlling both precursors and stromal cells and favors terminal differentiation of myeloid progenitors rather than proliferation.

Absence of galectin-3 does not affect the development of experimental tongue carcinomas in mice

BackgroundGalectin-3 is a lectin that presents pivotal roles in tumor biology and there are no studies evaluating their expression in dysplasias and carcinomas developed from tongue carcinogenesis models. AimsTo investigate the role of galectin-3 in the development of tongue carcinomas using a mouse model of oral carcinogenesis. MethodsGalectin-3-deficient (gal3−/−) and wild-type (gal3+/+) mice were challenged with 4-nitroquinoline-1-oxide in drinking water for 16weeks and killed at different times. Tongues were removed and the number of dysplasias and carcinomas was counted. An immunohistochemical study for galectin-3 was performed only in the tongue from gal3+/+ mice. ResultsIn both groups, a reduction of dysplasias and an increase of carcinomas from week 16 to week 32 (p>0.05) were observed. A predominance of high cytoplasmic and nuclear galectin-3 expression was observed in carcinomas (64.7%) and dysplasias (55.5%), respectively (p>0.05). The perilesional areas always presented a statistical cytoplasmic and nuclear galectin-3 overexpression. ConclusionsAbsence of galectin-3 did not directly affect the process of carcinogenesis and a cytoplasm shift of galectin-3 seems to be associated with development of tongue carcinomas.

Galectin-3 regulates peritoneal B1-cell differentiation into plasma cells

Extracellular galectin-3 participates in the control of B2 lymphocyte migration and adhesion and of their differentiation into plasma cells. Here, we analyzed the role of galectin-3 in B1-cell physiology and the balance between B1a and B1b lymphocytes in the peritoneal cavity. In galectin-3(-/-) mice, the total number of B1a lymphocytes was lower, while B1b lymphocyte number was higher as compared to wild-type mice. The differentiation of B1a cells into plasma cells was associated with their abnormal adhesion and location on the mesentery. The B220 and CD43, constitutively expressed by B1 lymphocytes, were respectively up- and downregulated in galectin-3(-/-) mice. Mononuclear cells were strongly adhered to the mesenteric membranes of both CD43(-/-) and galectin-3(-/-) mice, but in contrast to CD43(-/-) mice, the accumulation of B1 cells in peritoneal membranes in galectin-3(-/-) mice was accompanied by their functional differentiation into plasma cells. We have shown that in the absence of galectin-3, B1-cell differentiation into plasma cells is favored and the dynamic equilibrium of B1-cell populations in the peritoneum is maintained through a compensatory increase in B1b lymphocytes.

Lack of Galectin-3 Drives Response to Paracoccidioides brasiliensis toward a Th2-Biased Immunity

There is recent evidence that galectin-3 participates in immunity to infections, mostly by tuning cytokine production. We studied the balance of Th1/Th2 responses to P. brasiliensis experimental infection in the absence of galectin-3. The intermediate resistance to the fungal infection presented by C57BL/6 mice, associated with the development of a mixed type of immunity, was replaced with susceptibility to infection and a Th2-polarized immune response, in galectin-3-deficient (gal3−/−) mice. Such a response was associated with defective inflammatory and delayed type hypersensitivity (DTH) reactions, high IL-4 and GATA-3 expression and low nitric oxide production in the organs of infected animals. Gal3−/− macrophages exhibited higher TLR2 transcript levels and IL-10 production compared to wild-type macrophages after stimulation with P. brasiliensis antigens. We hypothesize that, during an in vivo P. brasiliensis infection, galectin-3 exerts its tuning role on immunity by interfering with the generation of regulatory macrophages, thus hindering the consequent Th2-polarized type of response.

Genetic assessment of the importance of galectin-3 in cancer initiation, progression, and dissemination in mice

The galectin family of beta-galactoside binding lectins is involved in normal and pathological processes. Altered expression of galectin-3 has been described in many cancers, and studies of cancer cell lines have implicated this lectin in various aspects of the tumorigenic cascade. The goal of this report was to directly assess the importance of galectin-3 in tumor biology by introducing the galectin-3 null mutation (galectin-3(-/-)) into mouse lines genetically programmed to develop cancers. We used two mouse models of human intestinal cancer, the Apc(Min) and Apc(1638N) lines, to study tumor initiation and tumor progression. We also crossed the galectin-3(-/-) mice with PyMT transgenic animals, a model in which primary mammary gland tumors give rise to lung metastases at high frequency. Unexpectedly, we show that the absence of galectin-3 does not affect the evolution of the disease in any of these three situations.

Role of Galectin-3 in Leukocyte Recruitment in a Murine Model of Lung Infection by Streptococcus pneumoniae

Pneumonia can be caused by a variety of pathogens, among which Streptococcus pneumoniae causes one of the most common forms of community-acquired pneumonia. Depending on the invading pathogen, the elements of the immune response triggered will vary. For most pathogens, such as Escherichia coli, neutrophil recruitment involves a well-described family of adhesion molecules, beta(2)-integrins. In the case of streptococcal pneumonia, however, neutrophil recruitment occurs mainly through a beta(2)-integrin-independent pathway. Despite decades of research on this issue, the adhesion molecules involved in neutrophil recruitment during lung infection by S. pneumoniae have not been identified. We have previously shown that galectin-3, a soluble mammalian lectin, can be found in lungs infected by S. pneumoniae, but not by E. coli, and can mediate the adhesion of neutrophils on the endothelial cell layer, implying its role in the recruitment of neutrophils to lungs infected with S. pneumoniae. In this study, using galectin-3 null mice, we report further evidence of the involvement of this soluble lectin in the recruitment of neutrophils to S. pneumonia-infected lungs. Indeed, in the absence of galectin-3, lower numbers of leukocytes, mainly neutrophils, were recruited to the infected lungs during infection by S. pneumoniae. In the case of beta(2)-integrin-dependent recruitment induced by lung infection with E. coli, the number of recruited neutrophils was not reduced. Thus, taken together, our data suggest that galectin-3 plays a role as a soluble adhesion molecule in the recruitment of neutrophils to lungs infected by S. pneumoniae, which induces beta(2)-integrin-independent migration.