Numerous regulatory programs have been identified that contribute to the restoration of homeostasis at the conclusion of immune responses and to safeguarding against the detrimental effects of ...chronic inflammation and autoimmune pathology. Malignant cells may usurp these pathways to create immunosuppressive networks that thwart antitumor responses. Herein we review the role of endogenous lectins (C-type lectins, siglecs, and galectins) and specific N- and O-glycans generated by the coordinated action of glycosyltransferases and glycosidases that together promote regulatory signals that control immune cell homeostasis. We also discuss the mechanisms by which glycan-dependent regulatory programs integrate into canonical circuits that amplify or silence immune responses related to autoimmunity and neoplastic disease.
Inflammation-mediated neurodegeneration occurs in the acute and the chronic phases of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Classically ...activated (M1) microglia are key players mediating this process. Here, we identified Galectin-1 (Gal1), an endogenous glycan-binding protein, as a pivotal regulator of M1 microglial activation that targets the activation of p38MAPK-, CREB-, and NF-κB-dependent signaling pathways and hierarchically suppresses downstream proinflammatory mediators, such as iNOS, TNF, and CCL2. Gal1 bound to core 2 O-glycans on CD45, favoring retention of this glycoprotein on the microglial cell surface and augmenting its phosphatase activity and inhibitory function. Gal1 was highly expressed in the acute phase of EAE, and its targeted deletion resulted in pronounced inflammation-induced neurodegeneration. Adoptive transfer of Gal1-secreting astrocytes or administration of recombinant Gal1 suppressed EAE through mechanisms involving microglial deactivation. Thus, Gal1-glycan interactions are essential in tempering microglial activation, brain inflammation, and neurodegeneration, with critical therapeutic implications for MS.
Display omitted
► Gal1 deactivates classically activated M1 microglia ► Gal1-glycan interactions promote retention of CD45 on the surface of microglial cells ► Lack of Gal1 favors classical microglial activation, inflammation, and neurodegeneration ► Astrocytes control microglial activation and neuroinflammation via Gal1
The clinical benefit conferred by vascular endothelial growth factors (VEGF)-targeted therapies is variable, and tumors from treated patients eventually reinitiate growth. Here, we identify a ...glycosylation-dependent pathway that compensates for the absence of cognate ligand and preserves angiogenesis in response to VEGF blockade. Remodeling of the endothelial cell (EC) surface glycome selectively regulated binding of galectin-1 (Gal1), which upon recognition of complex N-glycans on VEGFR2, activated VEGF-like signaling. Vessels within anti-VEGF-sensitive tumors exhibited high levels of α2-6-linked sialic acid, which prevented Gal1 binding. In contrast, anti-VEGF refractory tumors secreted increased Gal1 and their associated vasculature displayed glycosylation patterns that facilitated Gal1-EC interactions. Interruption of β1-6GlcNAc branching in ECs or silencing of tumor-derived Gal1 converted refractory into anti-VEGF-sensitive tumors, whereas elimination of α2-6-linked sialic acid conferred resistance to anti-VEGF. Disruption of the Gal1-N-glycan axis promoted vascular remodeling, immune cell influx and tumor growth inhibition. Thus, targeting glycosylation-dependent lectin-receptor interactions may increase the efficacy of anti-VEGF treatment.
Display omitted
Display omitted
•Hypoxia promotes glycan remodeling and binding of the lectin Gal1 to vascular cells•Glycosylation-dependent lectin-receptor interactions mimic VEGF-A function•Glycosylation of tumor-associated vessels delineates sensitivity to anti-VEGF•Targeting the Gal1-N-glycan axis overcomes anti-VEGF compensatory programs
Interactions between a lectin and carbohydrates on the VEGFR2 receptor enable ligand-independent signaling, establishing a mechanism underlying continued vessel growth in tumors treated with anti-VEGF antibodies.
Regulatory signals provide negative input to immunological networks promoting resolution of acute and chronic inflammation. Galectin-1 (Gal-1), a member of a family of evolutionarily conserved ...glycan-binding proteins, displays broad anti-inflammatory and proresolving activities by targeting multiple immune cell types. Within the innate immune compartment, Gal-1 acts as a resolution-associated molecular pattern by counteracting the synthesis of proinflammatory cytokines, inhibiting neutrophil trafficking, targeting eosinophil migration and survival, and suppressing mast cell degranulation. Likewise, this lectin controls T cell and B cell compartments by modulating receptor clustering and signaling, thus serving as a negative-regulatory checkpoint that reprograms cellular activation, differentiation, and survival. In this review, we discuss the central role of Gal-1 in regulatory programs operating during acute inflammation, autoimmune diseases, allergic inflammation, pregnancy, cancer, and infection. Therapeutic strategies aimed at targeting Gal-1-glycan interactions will contribute to overcome cancer immunosuppression and reinforce antimicrobial immunity, whereas stimulation of Gal-1-driven immunoregulatory circuits will help to mitigate exuberant inflammation.
The function of deciphering the biological information encoded by the glycome, which is the entire repertoire of complex sugar structures expressed by cells and tissues, is assigned in part to ...endogenous glycan-binding proteins or lectins. Galectins, a family of animal lectins that bind N-acetyllactosamine-containing glycans, have many roles in diverse immune cell processes, including those relevant to pathogen recognition, shaping the course of adaptive immune responses and fine-tuning the inflammatory response. How do galectins translate glycan-encoded information into tolerogenic or inflammatory cell programmes? An improved understanding of the mechanisms underlying these functions will provide further opportunities for developing new therapies based on the immunoregulatory properties of this multifaceted protein family.
Seasonal changes in disease activity have been observed in multiple sclerosis, an autoimmune disorder that affects the CNS. These epidemiological observations suggest that environmental factors ...influence the disease course. Here, we report that melatonin levels, whose production is modulated by seasonal variations in night length, negatively correlate with multiple sclerosis activity in humans. Treatment with melatonin ameliorates disease in an experimental model of multiple sclerosis and directly interferes with the differentiation of human and mouse T cells. Melatonin induces the expression of the repressor transcription factor Nfil3, blocking the differentiation of pathogenic Th17 cells and boosts the generation of protective Tr1 cells via Erk1/2 and the transactivation of the IL-10 promoter by ROR-α. These results suggest that melatonin is another example of how environmental-driven cues can impact T cell differentiation and have implications for autoimmune disorders such as multiple sclerosis.
Display omitted
•Melatonin levels negatively correlate with multiple sclerosis relapses in humans•Melatonin treatment ameliorates pathology in a mouse model of multiple sclerosis•Melatonin blocks ROR-γt expression and Th17 differentiation•Melatonin boosts Tr1 development via Erk1/2 and ROR-α
Melatonin affects the differentiation and function of effector and regulatory T cells in vitro and in vivo, representing an environmental cue that contributes to the seasonality of multiple sclerosis relapses and a potential target for therapeutic intervention in immune-mediated diseases.
Glycobiology of immune responses Rabinovich, Gabriel A.; van Kooyk, Yvette; Cobb, Brian A.
Annals of the New York Academy of Sciences,
April 2012, Letnik:
1253, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Unlike their protein “roommates” and their nucleic acid “cousins," carbohydrates remain an enigmatic arm of biology. The central reason for the difficulty in fully understanding how carbohydrate ...structure and biological function are tied is the nontemplate nature of their synthesis and the resulting heterogeneity. The goal of this collection of expert reviews is to highlight what is known about how carbohydrates and their binding partners—the microbial (non‐self), tumor (altered‐self), and host (self)—cooperate within the immune system, while also identifying areas of opportunity to those willing to take up the challenge of understanding more about how carbohydrates influence immune responses. In the end, these reviews will serve as specific examples of how carbohydrates are as integral to biology as are proteins, nucleic acids, and lipids. Here, we attempt to summarize general concepts on glycans and glycan‐binding proteins (mainly C‐type lectins, siglecs, and galectins) and their contributions to the biology of immune responses in physiologic and pathologic settings.
Highlights • Galectins engage a number of glycosylated immune checkpoint receptors. • Galectins alter T-cell and NK-cell activation, signaling and survival. • Galectins endow myeloid cells with ...immune regulatory potential. • Glycosylation-dependent galectin–receptor interactions control angiogenesis. • Galectin–glycan interactions confer resistance to anti-cancer therapies.
Galectins, β‐galactoside‐binding animal lectins, are differentially expressed by various immune cells as well as a wide range of other cell types. Extracellularly, galectins are able to exhibit ...bivalent or multivalent interactions with cell‐surface glycans on various immune cells and exert various effects. These include cytokine and mediator production, cell adhesion, apoptosis, and chemoattraction. In addition, they can form lattices with cell‐surface glycoprotein receptors, resulting in modulation of receptor functions, including clustering and endocytosis. Intracellularly, galectins can participate in signaling pathways and modulate biologic responses. These include apoptosis, cell differentiation, and cell migration. Thus, a large body of literature indicates that galectins play important roles in the immune and inflammatory responses through regulating the homeostasis and functions of immune cells. The use of mice deficient in individual galectins has provided additional evidence for the contributions of these proteins to these responses. Current research indicates that galectins play important roles in the development of acute inflammation as well as chronic inflammation associated with allergies, autoimmune diseases, atherosclerosis, infectious processes, and cancer. Thus, recombinant proteins or specific galectin inhibitors may be used as therapeutic agents for inflammatory diseases.
Galectins are a family of endogenous glycan-binding proteins that have crucial roles in a broad range of physiological and pathological processes. As a group, these proteins use both extracellular ...and intracellular mechanisms as well as glycan-dependent and independent pathways to reprogramme the fate and function of numerous cell types. Given their multifunctional roles in both tissue fibrosis and cancer, galectins have been identified as potential therapeutic targets for these disorders. Here, we focus on the therapeutic relevance of galectins, particularly galectin 1 (GAL1), GAL3 and GAL9 to tumour progression and fibrotic diseases. We consider an array of galectin-targeted strategies, including small-molecule carbohydrate inhibitors, natural polysaccharides and their derivatives, peptides, peptidomimetics and biological agents (notably, neutralizing monoclonal antibodies and truncated galectins) and discuss their mechanisms of action, selectivity and therapeutic potential in preclinical models of fibrosis and cancer. We also review the results of clinical trials that aim to evaluate the efficacy of galectin inhibitors in patients with idiopathic pulmonary fibrosis, nonalcoholic steatohepatitis and cancer. The rapid pace of glycobiology research, combined with the acute need for drugs to alleviate fibrotic inflammation and overcome resistance to anticancer therapies, will accelerate the translation of anti-galectin therapeutics into clinical practice.
PDF
