Tolerogenic signals delivered by dendritic cells to T cells through a galectin-1-driven immunoregulatory circuit involving interleukin 27 and interleukin 10.

Despite their central function in orchestrating immunity, dendritic cells (DCs) can respond to inhibitory signals by becoming tolerogenic. Here we show that galectin-1, an endogenous glycan-binding protein, can endow DCs with tolerogenic potential. After exposure to galectin-1, DCs acquired an interleukin 27 (IL-27)-dependent regulatory function, promoted IL-10-mediated T cell tolerance and suppressed autoimmune neuroinflammation. Consistent with its regulatory function, galectin-1 had its highest expression on DCs exposed to tolerogenic stimuli and was most abundant from the peak through the resolution of autoimmune pathology. DCs lacking galectin-1 had greater immunogenic potential and an impaired ability to halt inflammatory disease. Our findings identify a tolerogenic circuit linking galectin-1 signaling, IL-27-producing DCs and IL-10-secreting T cells, which has broad therapeutic implications in immunopathology.

The immunoregulatory glycan-binding protein galectin-1 triggers human platelet activation.

Platelet activation is a critical process during inflammation, thrombosis, and cancer. Here, we show that galectin-1, an endogenous lectin with immunoregulatory properties, plays a key role in human platelet activation and function. Galectin-1 binds to human platelets in a carbohydrate-dependent manner and synergizes with ADP or thrombin to induce platelet aggregation and ATP release. Furthermore, galectin-1 induces F-actin polymerization, up-regulation of P-selectin, and GPIIIa expression; promotes shedding of microvesicles; and triggers conformational changes in GPIIb/IIIa. In addition, exposure to this lectin favors the generation of leukocyte-platelet aggregates. A further mechanistic analysis revealed the involvement of Ca(2+) and cyclic nucleotide-dependent pathways in galectin-1-mediated control of platelet activation. Finally, expression of endogenous galectin-1 in human platelets contributes to ADP-induced aggregation. Our study reveals a novel unrecognized role for galectin-1 in the control of platelet physiology with potential implications in thrombosis, inflammation, and metastasis.

Galectin-1 as a potential therapeutic target in autoimmune disorders and cancer.

Galectin-1, a member of a family of highly conserved glycan-binding proteins, has emerged as a regulator of immune cell tolerance and homeostasis. This endogenous lectin widely expressed at sites of inflammation and tumour growth, has been postulated as an attractive immunosuppressive agent to restore immune cell tolerance and homeostasis in autoimmune and inflammatory settings. On the other hand, galectin-1 contributes to different steps of tumour progression including cell adhesion, migration and tumour-immune escape, suggesting that blockade of galectin-1 might result in therapeutic benefits in cancer. Recent findings implicating galectin-glycoprotein lattices as selective regulators of inflammatory responses have provided new insights into the understanding of the molecular bases of galectin-1-induced immunoregulation. Here the authors review the dual role of galectin-1 as a selective immunosuppressive agent in T helper (T(H))1 and T(H)17-mediated inflammatory/autoimmune disorders and a potential therapeutic target in cancer and metastasis.

Dissecting the pathophysiologic role of endogenous lectins: glycan-binding proteins with cytokine-like activity?

Several families of endogenous glycan-binding proteins have been implicated in a wide variety of immunological functions including first-line defence against pathogens, cell trafficking, and immune regulation. These include, among others, the C-type lectins (collectins, selectins, mannose receptor, and others), S-type lectins (galectins), I-type lectins (siglecs and others), P-type lectins (phosphomannosyl receptors), pentraxins, and tachylectins. This review will concentrate on the immunoregulatory roles of galectins (particularly galectin-1) and collectins (mannose-binding lectins and surfactant proteins) to illustrate the ability of endogenous glycan-binding proteins to act as cytokines, chemokines or growth factors, and thereby modulating innate and adaptive immune responses under physiological or pathological conditions. Understanding the pathophysiologic relevance of endogenous lectins in vivo will reveal novel targets for immunointervention during chronic infection, autoimmunity, transplantation and cancer.

A novel function for galectin-1 at the crossroad of innate and adaptive immunity: galectin-1 regulates monocyte/macrophage physiology through a nonapoptotic ERK-dependent pathway.

Several environmental factors can differentially regulate monocyte and macrophage response patterns, resulting in the display of distinct functional phenotypes. Galectin-1, an endogenous lectin found at peripheral lymphoid organs and inflammatory sites, has shown immunoregulatory activity in vivo in experimental models of autoimmunity and cancer. Whereas compelling evidence has been accumulated regarding the effects of galectin-1 on T cell fate, limited information is available on how galectin-1 may impact other immune cell types. In the present study, we report a novel role for galectin-1 in the regulation of monocyte and macrophage physiology. Treatment with galectin-1 in vitro differentially regulates constitutive and inducible FcgammaRI expression on human monocytes and FcgammaRI-dependent phagocytosis. In addition, galectin-1 inhibits IFN-gamma-induced MHC class II (MHC-II) expression and MHC-II-dependent Ag presentation in a dose-dependent manner. These regulatory effects were also evident in mouse macrophages recruited in response to inflammatory stimuli following treatment with recombinant galectin-1 and further confirmed in galectin-1-deficient mice. Investigation of the mechanisms involved in these functions showed that galectin-1 does not affect survival of human monocytes, but rather influences FcgammaRI- and MHC-II-dependent functions through active mechanisms involving modulation of an ERK1/2-dependent pathway. Our results provide evidence of a novel unrecognized role for galectin-1 in the control of monocyte/macrophage physiology with potential implications at the crossroad of innate and adaptive immunity.

Circulating anti-galectin-1 antibodies are associated with the severity of ocular disease in autoimmune and infectious uveitis.

PURPOSE: Galectin (Gal)-1, an endogenous lectin found at sites of immune privilege, plays a critical role in the regulation of the immune response. Therapeutic administration of Gal-1 or its genetic delivery suppresses chronic inflammation in experimental models of autoimmunity. The purpose of this work was to investigate the occurrence of circulating anti-Gal-1 antibodies in patients with autoimmune and infectious uveitis as potential determinant factors of disease progression. METHODS: IgG, IgE, and IgA anti-Gal-1 antibodies were assessed by ELISA and Western blot in sera from patients with autoimmune (n = 47) and infectious (n = 15) uveitis compared with healthy control subjects (n = 30). The frequency of anti-Gal-1 antibodies was examined in patients experiencing poor clinical outcome (n = 21) or good evolution (n = 9). Anti-Gal-1 antibodies were eluted by incubating patient sera with nitrocellulose filters adsorbed with rGal-1. The ability of these antibodies to recognize retinal tissue was assessed by ELISA, Western blot, and immunohistochemistry. RESULTS: IgE, IgG, and IgA anti-Gal-1 antibodies were increased in sera from patients with autoimmune uveitis (P < 0.001 vs. controls) and toxoplasmic retinochoroiditis (P < 0.001). The level of anti-Gal-1 IgE and IgG antibodies was associated with progressive disease and poor outcome in autoimmune and infectious uveitis. Furthermore, these antibodies strongly immunoreacted with retinal lysates and recognized retinal structures mainly photoreceptors in retinal sections. CONCLUSIONS: Anti-retinal Gal-1 antibodies are present in sera from patients with uveitis and can be associated with the progression of ocular disease, suggesting their potential use in follow-up observations of these patients.

Synthetic lactulose amines: novel class of anticancer agents that induce tumor-cell apoptosis and inhibit galectin-mediated homotypic cell aggregation and endothelial cell morphogenesis.

Galectins, a family of structurally related carbohydrate-binding proteins, contribute to different events associated with cancer biology, including apoptosis, homotypic cell aggregation, angiogenesis and tumor-immune escape. To interfere with galectin-carbohydrate interactions during tumor progression, a current challenge is the design of specific galectin inhibitors for therapeutic purposes. Here, we report the synthesis of three novel low molecular weight synthetic lactulose amines (SLA): (1) N-lactulose-octamethylenediamine (LDO), (2) N,N'-dilactulose-octamethylenediamine (D-LDO), and (3) N,N'-dilactulose-dodecamethylenediamine (D-LDD). These compounds showed a differential ability to inhibit binding of galectin-1 and/or galectin-3 to the highly glycosylated protein 90K in solid-phase assays. In addition, each compound demonstrated selective regulatory effects in different events linked to tumor progression including tumor-cell apoptosis, homotypic cell aggregation, and endothelial cell morphogenesis. Our results suggest that galectin inhibitors with subtle differences in their carbohydrate structures may be potentially used to specifically block different steps of tumor growth and metastasis.

Interacción entre proteínas y glicanos en la regulación fisiológica de las células T / How do protein-glycan interactions regulate T-cell physiology?

Recent evidence indicates that protein-glycan interactions play a critical role in different events associated with the physiology of T-cell responses including thymocyte maturation, T-cell activation, lymphocyte migration and T-cell apoptosis. Glycans decorating T-cell surface glycoproteins can modulate T-cell physiology by specifically interacting with endogenous lectins including selectins and galectins. These endogenous lectins are capable of recognizing sugar structures localized on T-cell surface glycoproteins and trigger different signal transduction pathways leading to differentiation, proliferation, cell cycle regulation or apoptosis. Protein-carbohydrate interactions may be controlled at different levels, including regulated expression of lectins during T-cell maturation and differentiation and the spatio-temporal regulation of glycosyltransferases and glycosidases, which create and modify sugar structures present in T-cell surface glycoproteins. This article briefly reviews the mechanisms by which protein-carbohydrate interactions modulate immunological processes such as T-cell activation, migration and apoptosis.

Las interacciones entre proteínas y glicanos juegan un papel fundamental en numerosos eventos de la regulación de la fisiología del sistema inmune, como maduración tímica, activación, migración y apoptosis de células T. Los carbohidratos son capaces de modular la fisiología linfocitaria a través de la interacción específica con lectinas endógenas como selectinas y galectinas. Estas lectinas endógenas son capaces de reconocer estructuras sacarídicas localizadas en glicoproteínas de la superficie celular y regular procesos tan diversos como proliferación, diferenciación y ciclo celular. Existen diversos niveles de control de la interacción entre lectinas y azúcares; en primer lugar podemos mencionar la expresión regulada de estas lectinas durante el desarrollo de una respuesta inmune, y en segundo lugar la regulación espacio-temporal de la actividad de glicosiltranferasas y glicosidasas cuya función es crear y modificar los azúcares específicos para estas lectinas. Existen evidencias de que la expresión y actividad de estas enzimas se regulan en forma positiva o negativa durante diferentes eventos del desarrollo, ejecución y finalización de la respuesta inmune. En este artículo se analizarán los mecanismos a través de los cuales las interacciones entre lectinas con sus carbohidratos específicos modulan en forma específica diversos procesos fisiológicos, como maduración de timocitos, migración linfocitaria, activación y diferenciación de células T y apoptosis.

Galectin-1 sensitizes resting human T lymphocytes to Fas (CD95)-mediated cell death via mitochondrial hyperpolarization, budding, and fission.

Galectins have emerged as a novel family of immunoregulatory proteins implicated in T cell homeostasis. Recent studies showed that galectin-1 (Gal-1) plays a key role in tumor-immune escape by killing antitumor effector T cells. Here we found that Gal-1 sensitizes human resting T cells to Fas (CD95)/caspase-8-mediated cell death. Furthermore, this protein triggers an apoptotic program involving an increase of mitochondrial membrane potential and participation of the ceramide pathway. In addition, Gal-1 induces mitochondrial coalescence, budding, and fission accompanied by an increase and/or redistribution of fission-associated molecules h-Fis and DRP-1. Importantly, these changes are detected in both resting and activated human T cells, suggesting that Gal-1-induced cell death might become an excellent model to analyze the morphogenetic changes of mitochondria during the execution of cell death. This is the first association among Gal-1, Fas/Fas ligand-mediated cell death, and the mitochondrial pathway, providing a rational basis for the immunoregulatory properties of Gal-1 in experimental models of chronic inflammation and cancer.