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15 pages, 1137 KB

Open AccessArticle

Differential Expression of Galectin-1 and Galectin-9 in Immune-Mediated Inflammatory Diseases

by Cristina Valero-Martínez, Marisa Pardines-Ortiz, Nuria Montes, Esteban Dauden, Benjamín Fernández-Gutierrez, Esther García-Planella, Fernando Gomollón García, Jordi Gratacós, Jose Javier Pérez-Venegas, Antonio Julía, Sara Marsal, Amalia Lamana, Rosario García-Vicuña, Isidoro González-Alvaro and Ana Triguero-Martínez

Int. J. Mol. Sci. 2025, 26(18), 9087; https://doi.org/10.3390/ijms26189087 - 18 Sep 2025

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Abstract

Galectin-1 and -9 (Gal1/9) are essential mediators of immune-inflammatory responses, which makes these proteins potential biomarkers for immune-mediated diseases (IMIDs), such as rheumatoid arthritis (RA), psoriasis (PS), psoriatic arthritis (PsA), inflammatory bowel disease, and systemic lupus erythematosus (SLE). Our aim was to evaluate [...] Read more.

Galectin-1 and -9 (Gal1/9) are essential mediators of immune-inflammatory responses, which makes these proteins potential biomarkers for immune-mediated diseases (IMIDs), such as rheumatoid arthritis (RA), psoriasis (PS), psoriatic arthritis (PsA), inflammatory bowel disease, and systemic lupus erythematosus (SLE). Our aim was to evaluate plasma Gal1/9 differences between IMID patients and healthy donors (HD). We analyzed 980 plasma samples divided into two analytical cohorts (600 discovery group and 380 validation group). Generalized linear models estimated Gal1/9 levels, adjusting for sex, age, storage time, and plate variability. In the overall IMID group, plasma Gal1 levels were comparable to those of HD, while Gal9 levels were significantly elevated. Levels varied across individual diseases: SLE patients consistently showed the highest Gal1/9 levels compared to both HD and other IMIDs, and RA patients had elevated Gal9 levels versus HD. Both Gal1 and Gal9 plasma levels correlated positively with higher disease activity, and Gal1 was higher in patients with longer disease duration. After adjustment for these confounders, SLE and RA patients maintained the highest Gal9 levels compared to HD. Our study demonstrates that Gal1 and Gal9 are differentially expressed across IMIDs, with particularly elevated levels in SLE, and both galectins are associated with disease activity. Full article

(This article belongs to the Special Issue Galectins (Gals), 2nd Edition)

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18 pages, 3246 KB

Open AccessArticle

Role of Endogenous Galectin-3 on Cell Biology of Immortalized Retinal Pigment Epithelial Cells In Vitro

by Caspar Liesenhoff, Marlene Hillenmayer, Caroline Havertz, Arie Geerlof, Daniela Hartmann, Siegfried G. Priglinger, Claudia S. Priglinger and Andreas Ohlmann

Int. J. Mol. Sci. 2025, 26(15), 7622; https://doi.org/10.3390/ijms26157622 - 6 Aug 2025

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Abstract

Galectin-3 is a multifunctional protein that is associated with diseases of the chorioretinal interface, in which the retinal pigment epithelium (RPE) plays a central role in disease development and progression. Since galectin-3 can function extracellularly as well as intracellularly via different mechanisms, we [...] Read more.

Galectin-3 is a multifunctional protein that is associated with diseases of the chorioretinal interface, in which the retinal pigment epithelium (RPE) plays a central role in disease development and progression. Since galectin-3 can function extracellularly as well as intracellularly via different mechanisms, we developed an immortalized human RPE cell line (ARPE-19) with a knockdown for galectin-3 expression (ARPE-19/LGALS3^+/−) using a sgRNA/Cas9 all-in-one expression vector. By Western blot analysis, a reduced galectin-3 expression of approximately 48 to 60% in heterozygous ARPE-19/LGALS3^+/− cells was observed when compared to native controls. Furthermore, ARPE-19/LGALS3^+/− cells displayed a flattened, elongated phenotype with decreased E-cadherin as well as enhanced N-cadherin and α-smooth muscle actin mRNA expression, indicating an epithelial–mesenchymal transition of the cells. Compared to wildtype controls, ARPE-19/LGALS3^+/− cells had significantly reduced metabolic activity to 86% and a substantially decreased proliferation to 73%. Furthermore, an enhanced cell adhesion and a diminished migration of immortalized galectin-3 knockdown RPE cells was observed compared to native ARPE-19 cells. Finally, by Western blot analysis, reduced pAKT, pERK1/2, and β-catenin signaling were detected in ARPE-19/LGALS3^+/− cells when compared to wildtype controls. In summary, in RPE cells, endogenous galectin-3 appears to be essential for maintaining the epithelial phenotype as well as cell biological functions such as metabolism, proliferation, or migration, effects that might be mediated via a decreased activity of the AKT, ERK1/2, and β-catenin signaling pathways. Full article

(This article belongs to the Special Issue Galectins (Gals), 2nd Edition)

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22 pages, 4282 KB

Open AccessArticle

Knockdown of TIM3 Hampers Dendritic Cell Maturation and Induces Immune Suppression by Modulating T-Cell Responses

by Shirui Chen, Junjie Chen, Yaojie Kong, Henghui Li, Zhinan Chen, Lingjie Luo, Yanwei Wu and Liang Chen

Int. J. Mol. Sci. 2025, 26(9), 4332; https://doi.org/10.3390/ijms26094332 - 2 May 2025

Cited by 1 | Viewed by 1561

Abstract

Various inhibitors targeting T-cell immunoglobulin and mucin-containing molecule 3 (TIM3) aimed at reversing T-cell exhaustion for better immunotherapy outcomes have demonstrated limited clinical efficacy as monotherapy, with the underlying mechanisms remaining ambiguous. TIM3 is markedly expressed in dendritic cells (DCs), and the inconsistent [...] Read more.

Various inhibitors targeting T-cell immunoglobulin and mucin-containing molecule 3 (TIM3) aimed at reversing T-cell exhaustion for better immunotherapy outcomes have demonstrated limited clinical efficacy as monotherapy, with the underlying mechanisms remaining ambiguous. TIM3 is markedly expressed in dendritic cells (DCs), and the inconsistent research findings on its role in myeloid cells underscore its vital function within DCs. Through the establishment of an in vitro differentiation model generating mature dendritic cells (mDCs) under TIM3-targeted interventions, combined with an RNA sequencing analysis, this investigation systematically examined TIM3-mediated regulation and ligand interactions in human primary DCs. The findings indicate that TIM3 inhibition hinders DC maturation, which subsequently diminishes the antigen-presenting capacity of DCs, ultimately leading to immune suppression in T cells. These findings collectively establish TIM3 as a regulator of DC differentiation that promotes DC maturation while optimizing the antigen-processing and presentation capacity. This study elucidates the rationale behind the suboptimal efficacy of TIM3 inhibitors and advocates for retaining TIM3 signaling pathways in DCs. Full article

(This article belongs to the Special Issue Galectins (Gals), 2nd Edition)

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18 pages, 7734 KB

Open AccessArticle

Characterization and Immune Functions of LcβLectin from Large Yellow Croaker (Larimichthys crocea): A Potential Antiviral Defense Molecule

by Jiawei Zhang, Hongling Wu, Ying Huang, Yao Yang, Dinaer Yekefenhazi, Wenzheng Zou and Fang Han

Int. J. Mol. Sci. 2025, 26(7), 3251; https://doi.org/10.3390/ijms26073251 - 31 Mar 2025

Cited by 2 | Viewed by 826

Abstract

Large yellow croaker iridovirus (LYCIV) poses a significant threat to the large yellow croaker (Larimichthys crocea) aquaculture industry due to its rapid transmission and high lethality. Galectins, as evolutionarily conserved carbohydrate-binding lectins and pattern recognition receptors (PRRs) in the innate immune [...] Read more.

Large yellow croaker iridovirus (LYCIV) poses a significant threat to the large yellow croaker (Larimichthys crocea) aquaculture industry due to its rapid transmission and high lethality. Galectins, as evolutionarily conserved carbohydrate-binding lectins and pattern recognition receptors (PRRs) in the innate immune system, play crucial roles in immune responses. In this study, we characterized the beta-galactoside-binding lectin from large yellow croaker (LcβLectin) and explored its potential as a disease resistance gene against LYCIV. The full-length cDNA of LcβLectin was cloned and found to contain conserved elements, such as β-galactoside-binding motifs, HNPR, and WCEEHR domains. Using L. crocea head-kidney macrophages (LCM10), we demonstrated that recombinant LcβLectin significantly inhibits LYCIV-induced cytopathic effects and reduces macrophage apoptosis, highlighting its key role in viral defense. Moreover, the overexpression of LcβLectin in LCM10 cells followed by transcriptomic analysis revealed its substantial regulatory effects on key immune-related signaling pathways, including C-type lectin signaling, p53 signaling, and Toll-like receptor signaling pathways. Collectively, our findings suggest that LcβLectin enhances fish resistance to viral diseases by augmenting immune system function and activating immune-related pathways, providing valuable insights into the innate immune mechanisms of aquatic species and potential strategies for disease prevention in aquaculture. Full article

(This article belongs to the Special Issue Galectins (Gals), 2nd Edition)

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Review

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20 pages, 1215 KB

Open AccessReview

Association of Elevated Galectin-4 Concentrations with Obesity, Diabetes, and Cardiovascular Diseases

by Krystian Kozak and Monika Zajkowska

Int. J. Mol. Sci. 2025, 26(19), 9402; https://doi.org/10.3390/ijms26199402 - 26 Sep 2025

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Abstract

Obesity, type 2 diabetes mellitus (T2DM), and cardiovascular diseases (CVDs) represent major global health burdens with overlapping pathophysiological mechanisms, including chronic low-grade inflammation, oxidative stress, and gut microbiota dysbiosis. Galectins, a family of β-galactoside-binding lectins, have been implicated in immune regulation, inflammation, and [...] Read more.

Obesity, type 2 diabetes mellitus (T2DM), and cardiovascular diseases (CVDs) represent major global health burdens with overlapping pathophysiological mechanisms, including chronic low-grade inflammation, oxidative stress, and gut microbiota dysbiosis. Galectins, a family of β-galactoside-binding lectins, have been implicated in immune regulation, inflammation, and tissue remodeling. Among them, Galectin-4 (Gal-4), primarily expressed in the gastrointestinal tract, has emerged as a potential biomarker due to its roles in epithelial integrity, inflammatory signaling, and metabolic regulation. Despite its established involvement in cancer and inflammatory disease, the relevance of Gal-4 in cardiometabolic disorders remains poorly defined. A comprehensive literature search was conducted via the PubMed and ScienceDirect databases. The association between Gal-4 and obesity has been reported, indicating that elevated Gal-4 levels correlate with obesity, but primarily in individuals with diabetes. Circulating Gal-4 concentrations are consistently elevated in diabetic populations. In CVD, elevated Gal-4 levels are associated with ischemic heart disease, heart failure, aortic stenosis, carotid atherosclerosis, and adverse outcomes following myocardial infarction and stroke. Furthermore, prospective studies link Gal-4 to increased risk of cardiovascular events and mortality, underscoring its potential prognostic relevance. Available evidence regarding the mechanistic role of Gal-4 in the pathogenesis of obesity, diabetes, and cardiovascular disease remains limited; therefore, future studies should address whether Gal-4 actively contributes to cardiometabolic dysfunction or only reflects secondary inflammatory or fibrotic processes. Elucidating the biological functions of Gal-4 may provide insight into its utility in diagnostics and support the development of novel therapeutic strategies for cardiometabolic disorders. Full article

(This article belongs to the Special Issue Galectins (Gals), 2nd Edition)

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38 pages, 2308 KB

Open AccessReview

Galectin-9—An Emerging Glyco-Immune Checkpoint Target for Cancer Therapy

by Anastasia Iris Karkempetzaki, Tobias Schatton and Steven R. Barthel

Int. J. Mol. Sci. 2025, 26(16), 7998; https://doi.org/10.3390/ijms26167998 - 19 Aug 2025

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Abstract

Galectin-9 (Gal-9, LGALS9) is a member of the family of carbohydrate-binding lectins known as galectins. Galectins bind a diverse repertoire of galactose-bearing glycoprotein receptors expressed across multiple cell types. These interactions elicit a broad spectrum of pleiotropic effects important in both normal [...] Read more.

Galectin-9 (Gal-9, LGALS9) is a member of the family of carbohydrate-binding lectins known as galectins. Galectins bind a diverse repertoire of galactose-bearing glycoprotein receptors expressed across multiple cell types. These interactions elicit a broad spectrum of pleiotropic effects important in both normal physiology and disease pathogenesis. Gal-9 contains two separate carbohydrate recognition domains with overlapping yet also divergent binding affinities for distinct glycostructures. This tandem repeat motif enables fine-tuning of its various biological functions. Additional control of Gal-9 activity is provided via multiple gene variants, protein isoforms, tissue distribution, and cell type-associated glycoprotein binding profiles. Within the tumor microenvironment, Gal-9 interacts with immune, non-immune, and cancer cells to influence malignant progression. Its binding of the premier immune checkpoint glycoreceptors, T-cell immunoglobulin and mucin-domain-containing-3 (TIM-3) and programmed cell death protein 1 (PD-1), places Gal-9 apart as a burgeoning target for immunotherapy. In this review, we delve into important aspects of Gal-9 immunobiology in tumorigenesis, including glycobiological and lineage-dependent functions. We further examine Gal-9 as a promising new glyco-immune checkpoint target for cancer therapy. Full article

(This article belongs to the Special Issue Galectins (Gals), 2nd Edition)

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19 pages, 2916 KB

Open AccessReview

Inflammaging-Driven Osteoporosis: Is a Galectin-Targeted Approach Needed?

by Marina Russo, Caterina Claudia Lepre, Annalisa Itro, Gabriele Martin, Gianluca Conza, Maria Consiglia Trotta, Monica Puticiu, Anca Hermenean, Francesca Gimigliano, Michele D’Amico and Giuseppe Toro

Int. J. Mol. Sci. 2025, 26(13), 6473; https://doi.org/10.3390/ijms26136473 - 4 Jul 2025

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Abstract

Osteoporosis (OP) is a chronic disease characterized by reduced bone mass and altered microarchitecture, leading to bone fragility and fractures. Due to its high morbidity, disability, and healthcare costs, identifying new biomarkers and therapeutic strategies is crucial for improving OP diagnosis and prevention. [...] Read more.

Osteoporosis (OP) is a chronic disease characterized by reduced bone mass and altered microarchitecture, leading to bone fragility and fractures. Due to its high morbidity, disability, and healthcare costs, identifying new biomarkers and therapeutic strategies is crucial for improving OP diagnosis and prevention. In this context, this narrative review aims to depict the role of carbohydrate-binding proteins Galectins (Gals) in the combined processes of inflammation and aging contributing to bone fragility by exploring their potential as novel therapeutic targets for OP. Full article

(This article belongs to the Special Issue Galectins (Gals), 2nd Edition)

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25 pages, 1575 KB

Open AccessReview

Galectin-3—Insights from Inflammatory Bowel Disease and Primary Sclerosing Cholangitis

by Thomas Grewal, Hauke Christian Tews and Christa Buechler

Int. J. Mol. Sci. 2025, 26(13), 6101; https://doi.org/10.3390/ijms26136101 - 25 Jun 2025

Cited by 1 | Viewed by 1342

Abstract

Inflammatory bowel disease (IBD) and primary sclerosing cholangitis (PSC) are related diseases with poorly understood pathophysiology. While therapy options for IBD have increased, treatment options for PSC remain limited. Galectin-3 is a multifunctional lectin expressed in intestinal epithelial cells, and is abundant in [...] Read more.

Inflammatory bowel disease (IBD) and primary sclerosing cholangitis (PSC) are related diseases with poorly understood pathophysiology. While therapy options for IBD have increased, treatment options for PSC remain limited. Galectin-3 is a multifunctional lectin expressed in intestinal epithelial cells, and is abundant in immune cells such as macrophages, with roles in cell adhesion, apoptosis, inflammation and fibrosis being associated with IBD and PSC disease development and progression. In addition, galectin-3 is also a visceral fat-derived protein whose systemic levels are increased in obese individuals, the latter correlating with a poorer prognosis in IBD and PSC patients. On the other hand, decreased galectin-3 expression in the inflamed mucosal tissues of mice and patients with IBD possibly indicate a protective role of this lectin in IBD. However, galectin-3 loss or inhibition is protective in most animal models of liver fibrosis but exacerbates the severity of autoimmune liver disease. Hence, with PSC being a slowly progressing autoimmune hepatobiliary disease closely related to IBD, further studies evaluating galectin-3 as a therapeutic target or biomarker for the severity of IBD and the occurrence of PSC are still needed. This review summarizes studies that have analyzed expression patterns and functions of galectin-3 in IBD and PSC. Current evidence suggests that strategies to block galectin-3 are not advised for patients with IBD and PSC-IBD. Full article

(This article belongs to the Special Issue Galectins (Gals), 2nd Edition)

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