Endogenous galectins and the control of the host inflammatory response

Norling, Lucy V.; Perretti, Mauro; Cooper, Dianne

doi:10.1677/joe-08-0512

Cited by 81 publications

(87 citation statements)

References 146 publications

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“…The analysis of the existence of redundant or antagonistic functions between Gals is a major concern, because these proteins can converge under normal or pathological conditions, such as inflammatory foci or certain tumors (16)(17)(18)(19). The proapoptotic activity of Gal-1 and Gal-3 has been extensively characterized, although most experiments were performed using activated T cells or T cell lines.…”

mentioning

confidence: 99%

Redundant and Antagonistic Functions of Galectin-1, -3, and -8 in the Elicitation of T Cell Responses

Tribulatti

Figini

Carabelli

et al. 2012

The Journal of Immunology

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Galectins, a family of mammalian lectins, have emerged as key regulators of the immune response. We previously demonstrated that galectin (Gal)-8, from the tandem-repeat subgroup, exerts two well-defined effects on mouse naive peripheral CD4 T cells: Ag-specific costimulation and Ag-independent proliferation. These stimulatory signals on naive T cells have not been described for any other Gal. Therefore, we investigated whether Gal-1 and Gal-3, two prominent members of the Gal family, share the stimulatory effects exerted by Gal-8 on naive T cells. We found that Gal-1 costimulated Ag-specific T cell responses similarly to Gal-8, as evaluated in the DO11.10 TCROVA-transgenic mouse model, by acting simultaneously on APCs and target CD4 T cells. In contrast, Gal-3 failed to costimulate Ag-specific T cell responses; moreover, it antagonized both Gal-1 and Gal-8 signals. We observed that both Gal-1 and Gal-3 were unable to induce Ag-independent proliferation; however, when two Gal-1 molecules were covalently fused, the resulting chimeric protein efficiently promoted proliferation. This finding indicates that Gal-1 might eventually induce proliferation and, moreover, stresses the requirement of a tandem-repeat structure. Remarkably, a single dose of recombinant Gal-1 or Gal-8 administered together with a suboptimal Ag dose to DO11.10 mice strengthened weak responses in vivo. Taken together, these findings argue for the participation of Gals in the initiation of the immune response and allow the postulation of these lectins as enhancers of borderline Ag responses, thus representing potential adjuvants for vaccine formulations.

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confidence: 99%

Redundant and Antagonistic Functions of Galectin-1, -3, and -8 in the Elicitation of T Cell Responses

Tribulatti

Figini

Carabelli

et al. 2012

The Journal of Immunology

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“…They can function intracellularly and extracellularly. Accumulating evidence implicates galectins as immunoregulatory mediators in diverse physiological and pathological processes such as immune and inflammatory responses, tumor immunity, wound repair, and atherosclerosis (2,3).…”

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confidence: 99%

“…Galectin-9 exerts its immunosuppressive roles through its receptor, T cell immunoglobin domain and mucin domain 3 (Tim3), 2 which can increase the survival of transplants (6, 8 -11). Galectin-9 may also induce proinflammatory cytokines in monocytes and T cells in a Tim3-independent manner (12,13).…”

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confidence: 99%

Galectin-9 Protein Expression in Endothelial Cells Is Positively Regulated by Histone Deacetylase 3

Alam

Margariti

et al. 2011

Journal of Biological Chemistry

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Galectin-9 expression in endothelial cells can be induced in response to inflammation. However, the mechanism of its expression remains unclear. In this study, we found that interferon-␥ (IFN-␥) induced galectin-9 expression in human endothelial cells in a time-dependent manner, which coincided with the activation of histone deacetylase (HDAC). When endothelial cells were treated with the HDAC3 inhibitor, apicidin, or shRNA-HDAC3 knockdown, IFN-␥-induced galectin-9 expression was abolished. Overexpression of HDAC3 induced the interaction between phosphoinositol 3-kinase (PI3K) and IFN response factor 3 (IRF3), leading to IRF3 phosphorylation, nuclear translocation, and galectin-9 expression. HDAC3 functioned as a scaffold protein for PI3K/IRF3 interaction. In addition to galectin-9 expression, IFN-␥ also induced galectin-9 location onto plasma membrane, which was HDAC3-independent. Importantly, HDAC3 was essential for the constitutive transcription of PI3K and IRF3, which might be responsible for the basal level of galectin-9 expression. The phosphorylation of IRF3 was essential for galectin-9 expression. This study provides new evidence that HDAC3 regulates galectin-9 expression in endothelial cells via interaction with PI3K-IRF3 signal pathway.Galectins are a family of lectins classified into three groups (prototype, tandem-repeat, and chimera-type galectins) according to their conserved carbohydrate recognition domains and their ability to bind to ␤-galactosides (1). To date, 15 galectin proteins have been identified in mammals displaying wide tissue distribution whereas some have higher tissue specificity. They can function intracellularly and extracellularly. Accumulating evidence implicates galectins as immunoregulatory mediators in diverse physiological and pathological processes such as immune and inflammatory responses, tumor immunity, wound repair, and atherosclerosis (2, 3).Galectin-9 belongs to the tandem-repeat galectins that contain two carbohydrate recognition domains, mainly functioning as a chemoattractant of eosinophils (4, 5) and immunomodulation in a physiological and pathological setting (6, 7). Galectin-9 exerts its immunosuppressive roles through its receptor, T cell immunoglobin domain and mucin domain 3 (Tim3), 2 which can increase the survival of transplants (6, 8 -11). Galectin-9 may also induce proinflammatory cytokines in monocytes and T cells in a Tim3-independent manner (12, 13). Galectin-9-deficient mice show enhanced susceptibility to arthritic induction with increased CD4 ϩ TIM3 ϩ cells (14) and were prone to increased mortality and died within 72 h of LPS induction (15). In endothelial cells, galectin-9 can be induced by interferon-␥ (IFN-␥) (16, 17) and double-stranded RNA (18), which may play a role in inflammatory response by regulating interactions between the vascular wall and eosinophils. However, the mechanism of how galectin-9 is expressed in endothelial cells is unknown.Histone deacetylase 3 (HDAC3) belongs to class I HDAC family (19). Distinct from other family membe...

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“…45 For example, galectin-1 induces apoptosis of activated effector CD4 þ T-helper 1 and 17 cells (Th1 and Th17), but not naïve T cells, T-helper 2 lymphocytes (Th2), or regulatory T cells. 46,47 In addition, galectin-1 can also modulate T-cell expression of inflammatory and anti-inflammatory cytokines.…”

Section: Galectin-1 Delivery For Immunosuppression and Immune Tolerancementioning

confidence: 99%

Engineering galectin–glycan interactions for immunotherapy and immunomodulation

Farhadi

Hudalla

2016

Exp Biol Med (Maywood)

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Galectins, a 15-member family of soluble carbohydrate-binding proteins, are receiving increasing interest as therapeutic targets for immunotherapy and immunomodulation due to their role as extracellular signals that regulate innate and adaptive immune cell phenotype and function. However, different galectins can have redundant, synergistic, or antagonistic signaling activity in normal immunological responses, such as resolution of inflammation and induction of antigen-specific tolerance. In addition, certain galectins can be hijacked to promote progression of immunopathologies, such as tumor immune privilege, metastasis, and viral infection, while others can inhibit these processes. Thus, eliciting a desired immunological outcome will likely necessitate therapeutics that can precisely enhance or inhibit particular galectin-glycan interactions. Multivalency is an important determinant of the affinity and specificity of natural galectin-glycan interactions, and is emerging as a key design element for therapeutics that can effectively manipulate galectin bioactivity. This minireview surveys current molecular and biomaterial engineering approaches to create therapeutics that can stabilize galectin multivalency or recapitulate natural glycan multivalency (i.e. ''the glycocluster effect''). In particular, we highlight examples of using natural and engineered multivalent galectins for immunosuppression and immune tolerance, with a particular emphasis on treating autoimmune diseases or avoiding transplant rejection. In addition, we present examples of multivalent inhibitors of galectin-glycan interactions to maintain or restore T-cell function, with a particular emphasis on promoting antitumor immunity. Finally, we discuss emerging opportunities to further engineer galectin-glycan interactions for immunotherapy and immunomodulation.

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Endogenous galectins and the control of the host inflammatory response

Cited by 81 publications

References 146 publications

Redundant and Antagonistic Functions of Galectin-1, -3, and -8 in the Elicitation of T Cell Responses

Redundant and Antagonistic Functions of Galectin-1, -3, and -8 in the Elicitation of T Cell Responses

Galectin-9 Protein Expression in Endothelial Cells Is Positively Regulated by Histone Deacetylase 3

Engineering galectin–glycan interactions for immunotherapy and immunomodulation

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