Control of intestinal inflammation by glycosylation-dependent lectin-driven immunoregulatory circuits

Morosi, Luciano Gastón; Cutine, Anabela María; Cagnoni, Alejandro J.; Cocco, Montana N Manselle; Croci, Diego O.; Merlo, Joaquín Pedro; Morales, Rosa María; May, María; Pérez-Sáez, Juan M.; Girotti, María Romina; Méndez-Huergo, Santiago P.; Pucci, Betiana; Gil, Aníbal H.; Huernos, Sergio P.; Docena, Guillermo Horacio; Sambuelli, Alicia M.; Toscano, Marta A.; Rabinovich, Gabriel A.; Mariño, Karina

doi:10.1126/sciadv.abf8630

Cited by 16 publications

(8 citation statements)

References 72 publications

(115 reference statements)

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“…Accordingly, commensal gut microorganisms were shown to promote the expression of Fut2 gene (that encodes α1,2‐fucosyltransferase 2) in intestinal epithelial cells, increasing the expression of α1,2‐fucose, through the activation of type 3 innate lymphoid cells (ILC3)/IL22 axis, an essential glycogene to assure gut homeostasis [103]. Recently, in colonic biopsies of IBD patients, it was described that upregulation of ST6GAL1 gene, that encodes a α2,6‐sialyltransferase 1, resulted in the inhibition of Galectin (Gal)‐1 binding [104]. This suggests that glycosylation regulates the activity of Gal‐1, a β‐galactoside‐binding protein involved in a variety of biological processes that controls both innate and adaptive cells response, being essential to maintain the gut homeostasis [104].…”

Section: Role Of Glycans In the Breach Of Immune Tolerancementioning

confidence: 99%

“…Recently, in colonic biopsies of IBD patients, it was described that upregulation of ST6GAL1 gene, that encodes a a2,6-sialyltransferase 1, resulted in the inhibition of Galectin (Gal)-1 binding [104]. This suggests that glycosylation regulates the activity of Gal-1, a b-galactoside-binding protein involved in a variety of biological processes that controls both innate and adaptive cells response, being essential to maintain the gut homeostasis [104]. Regarding b1,6-GlcNAc branched N-glycans, it has been shown that Mgat5 -/mice exhibit increased susceptibility to develop severe forms of colitis (IBD), as well as experimental autoimmune encephalomyelitis (EAE), an autoimmune disease with clinical similarities to MS [105,106].…”

Section: Altered Self-glycans As Instructors Of Autoreactive Immune R...mentioning

confidence: 99%

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Glycans as a key factor in self and nonself discrimination: impact on the breach of immune tolerance

et al. 2022

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Glycans are carbohydrates that are made by all organisms and covalently conjugated to other biomolecules. Glycans cover the surface of both human cells and pathogens and are fundamental to defining the identity of a cell or an organism, thereby contributing to discriminating self from nonself. As such, glycans are a class of ‘Self‐Associated Molecular Patterns’ that can fine‐tune host inflammatory processes. In fact, glycans can be sensed and recognized by a variety of glycan‐binding proteins (GBP) expressed by immune cells, such as galectins, siglecs, and C‐type lectins, which recognize changes in the cellular glycosylation, instructing both pro‐inflammatory and anti‐inflammatory responses. In this review, we introduce glycans as cell‐identification structures, discussing how glycans modulate host–pathogen interactions and how they can fine‐tune inflammatory processes associated with infection, inflammation and autoimmunity. Finally, from the clinical standpoint, we discuss how glycoscience research can benefit life sciences and clinical medicine by providing a source of valuable biomarkers and therapeutic targets for immunity.

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Section: Role Of Glycans In the Breach Of Immune Tolerancementioning

confidence: 99%

Section: Altered Self-glycans As Instructors Of Autoreactive Immune R...mentioning

confidence: 99%

Glycans as a key factor in self and nonself discrimination: impact on the breach of immune tolerance

et al. 2022

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“…It has been shown that ST6GAL1 could prevent intestinal inflammation by regulating T cell immunity levels and play a protective effect on IgA nephropathy by inhibiting the production of proinflammatory cytokines in patients. 15,16 While the deficiency of ST6GAL1 could cause exaggerated acute neutrophilic inflammation, increase radiation-induced gastrointestinal damage, and promote the transformation of synovial fibroblasts into a pro-inflammatory phenotype in mice. [17][18][19] For HCC, it has been reported that serum ST6GAL1 levels were positively correlated with tumor FGF19 expression in patients with surgically resected HCC, and could be a novel serum biomarker for lenvatinib-susceptible FGF19-driven HCC.…”

Section: Introductionmentioning

confidence: 99%

Downregulation of ST6GAL1 Promotes Liver Inflammation and Predicts Adverse Prognosis in Hepatocellular Carcinoma

Liu¹,

Cao²,

Liang³

et al. 2022

JIR

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Background Hepatocellular carcinoma (HCC) is one of the most malignant tumors worldwide. The ST6 β-galactoside α-2, 6-sialyltransferase 1 (ST6GAL1) has been found aberrantly expressed in a variety of cancers including HCC, but its function and mechanism in regulating liver inflammation remain to be investigated. This study aimed to explore the role of ST6GAL1 in HCC. The data of ST6GAL1 expression, prognosis, and clinical parameters were collected and further analyzed from the public databases including The Cancer Genome Atlas (TCGA), Human Protein Atlas (HPA), and Gene Expression Omnibus (GEO). The HCC rat model was constructed by intraperitoneal injection of diethylnitrosamine. The mRNA and protein expression levels of ST6GAL1 in rat liver tissues were detected by real-time quantitative polymerase chain reaction, capillary electrophoresis, and Western blot. Results The ST6GAL1 mRNA and protein expression levels were both lower in HCC tissues compared with normal liver tissues in the public databases and HCC rat model. The survival analysis showed that upregulation of ST6GAL1 was an independent prognostic factor for good prognosis in HCC patients. The ST6GAL1 mRNA expression showed a negative correlation with ST6GAL1 methylation levels. Enrichment analysis showed that ST6GAL1 expression was most associated with metabolic, cancer, estrogen, axon guidance, cAMP, and PI3K-AKT signaling pathways. The ST6GAL1 mRNA expression negatively correlated with liver inflammation status and proportion of NK CD56bright, NK CD56dim, pDC, and CD8+ T cells in liver. Conclusion Compared with normal tissues, ST6GAL1 was lower expressed in HCC tumor tissues, and the downregulation of ST6GAL1 was associated with a poor prognosis in HCC patients. ST6GAL1 could further affect the infiltration of immune cells to exert anti-inflammation function in liver. Our study indicated that ST6GAL1 could be a potential biomarker and therapeutic target to assess the prognosis and regulate the immune cells infiltration level of HCC.

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“…Further structural, cellular and glycomic studies of these new complexes are needed to demonstrate a universal allosteric mechanism of regulation for Galectins functions. Moreover, taking into account Galectins involvement in many crucial pathologies such as cancer 6,48 and inflammation 49 or infection by pathogens 7 , the discovery of this selectivity switch should also increase the potential to develop molecules modulating Gal-1 interactions and function in specific pathological situations.…”

Section: Discussionmentioning

confidence: 99%

Pre-B cell receptor acts as a selectivity switch for Galectin-1 at the pre-B cell surface

Touarin

Serrano

Courbois

et al. 2022

Preprint

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Galectins are glycan binding proteins translating the sugar-encoded information of cellular glycoconjugates into many physiological activities including immunity, cell migration, and signaling. During early B lymphocytes (BL) development at the pre-B cell stage, BL express the pre-B cell receptor (pre-BCR) and are supported by mesenchymal stromal cells secreting Galectin-1 (Gal-1). Gal-1 interacts with glycosylated receptors from stromal and pre-B cell surfaces but also with the pre-BCR through a direct carbohydrate-independent contact. How this interaction might interplay with the glycan-decoding function of Gal-1 is unknown. Here, we investigated Gal-1 binding to cell surface ligands using NMR spectroscopy on native membranes. We showed that pre-BCR regulates Gal-1 binding to specifically target α2,3-sialylated receptors on pre-B cells. Upon pre-BCR interaction, dynamic changes resulted in additional contacts with α2,3-sialylated glycans converting Gal-1 from an exo- to an endo-type lectin. Remarkably, this selectivity switch is able to promote pre-B cell survival. Altogether, we shed light on a new mechanism allowing fine-tuning of Galectin specificity at the cell surfaces.

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Control of intestinal inflammation by glycosylation-dependent lectin-driven immunoregulatory circuits

Cited by 16 publications

References 72 publications

Glycans as a key factor in self and nonself discrimination: impact on the breach of immune tolerance

Glycans as a key factor in self and nonself discrimination: impact on the breach of immune tolerance

Downregulation of ST6GAL1 Promotes Liver Inflammation and Predicts Adverse Prognosis in Hepatocellular Carcinoma

Pre-B cell receptor acts as a selectivity switch for Galectin-1 at the pre-B cell surface

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