Disruption of hepatocyte Sialylation drives a T cell-dependent pro-inflammatory immune tone

Oswald, Douglas M.; Zhou, Julie Y.; Jones, Mark B.; Cobb, Brian A.

doi:10.1007/s10719-020-09918-y

Cited by 16 publications

(14 citation statements)

References 47 publications

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“…A previous study has found that knocking out the ST6GAL1 gene of hepatocytes could promote immune response and inflammation in liver. 35 Our analysis also found that ST6GAL1 was lower expressed in VH-related HCC and AH-related HCC. And downregulation of ST6GAL1 was associated with liver inflammation levels, which indicated its anti-inflammation function in liver.…”

Section: Discussionsupporting

confidence: 66%

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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Section: Discussionsupporting

confidence: 66%

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

Liu¹,

Cao²,

Liang³

et al. 2022

JIR

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“…Findings from our study reveal that both core 2 O-glycans and α(2,6) sialylation play essential roles in modulating intestinal inflammation as has been described previously for other tissues, including the fetal-maternal unit and the liver ( 57 , 58 ). Our in vivo studies featuring the TNBS-induced colitis model revealed decreased α(2,6) sialylation in colonic CD8 + T cells; these findings indicate that aberrant T cell responses may be suppressed through a glycan-dependent mechanism ( Fig.…”

Section: Discussionsupporting

confidence: 80%

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

et al. 2021

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Diverse immunoregulatory circuits operate to preserve intestinal homeostasis and prevent inflammation. Galectin-1 (Gal1), a β-galactoside–binding protein, promotes homeostasis by reprogramming innate and adaptive immunity. Here, we identify a glycosylation-dependent “on-off” circuit driven by Gal1 and its glycosylated ligands that controls intestinal immunopathology by targeting activated CD8+ T cells and shaping the cytokine profile. In patients with inflammatory bowel disease (IBD), augmented Gal1 was associated with dysregulated expression of core 2 β6-N-acetylglucosaminyltransferase 1 (C2GNT1) and α(2,6)-sialyltransferase 1 (ST6GAL1), glycosyltransferases responsible for creating or masking Gal1 ligands. Mice lacking Gal1 exhibited exacerbated colitis and augmented mucosal CD8+ T cell activation in response to 2,4,6-trinitrobenzenesulfonic acid; this phenotype was partially ameliorated by treatment with recombinant Gal1. While C2gnt1−/− mice exhibited aggravated colitis, St6gal1−/− mice showed attenuated inflammation. These effects were associated with intrinsic T cell glycosylation. Thus, Gal1 and its glycosylated ligands act to preserve intestinal homeostasis by recalibrating T cell immunity.

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“…Paradoxical as this may seem with respect to galectin inhibition, this clearly demonstrates that galectins are not sufficient to carry T cell immunosuppression alone. This is consistent with the recent discovery that liver macrophages expressing the α2,6-sialic acid-specific Siglec, CD22, can inhibit α2,6-sialic acid decorated T cells, which provides an alternative liver-driven mechanism for maintaining systemic immune homeostasis ( 184 ). APCs also have a key role in T cell polarization and activation.…”

Section: Adaptive Immunitysupporting

confidence: 90%

N-Glycosylation and Inflammation; the Not-So-Sweet Relation

Radovani

Gudelj²

2022

Front. Immunol.

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Chronic inflammation is the main feature of many long-term inflammatory diseases such as autoimmune diseases, metabolic disorders, and cancer. There is a growing number of studies in which alterations of N-glycosylation have been observed in many pathophysiological conditions, yet studies of the underlying mechanisms that precede N-glycome changes are still sparse. Proinflammatory cytokines have been shown to alter the substrate synthesis pathways as well as the expression of glycosyltransferases required for the biosynthesis of N-glycans. The resulting N-glycosylation changes can further contribute to disease pathogenesis through modulation of various aspects of immune cell processes, including those relevant to pathogen recognition and fine-tuning the inflammatory response. This review summarizes our current knowledge of inflammation-induced N-glycosylation changes, with a particular focus on specific subsets of immune cells of innate and adaptive immunity and how these changes affect their effector functions, cell interactions, and signal transduction.

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Disruption of hepatocyte Sialylation drives a T cell-dependent pro-inflammatory immune tone

Cited by 16 publications

References 47 publications

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

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

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

N-Glycosylation and Inflammation; the Not-So-Sweet Relation

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