Altered granulopoietic profile and exaggerated acute neutrophilic inflammation in mice with targeted deficiency in the sialyltransferase ST6Gal I

Nasirikenari, Mehrab; Segal, Brahm H.; Ostberg, Julie R.; Urbasic, Ashlee; Lau, Joseph T.Y.

doi:10.1182/blood-2006-04-014779

Cited by 68 publications

(95 citation statements)

References 59 publications

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“…Thus, Siat1⌬P1 mice might lack the particular subset of B cells that produce sialylated Fc glycans. Indeed, circulatory ST6Gal-1 deficiency has been attributed to altered hematopoietic activity in bone marrow (11,12,16). IgG acquires antiinflammatory properties upon Fc sialylation.…”

Section: Discussionmentioning

confidence: 99%

“…Our laboratory has demonstrated that ST6Gal-1 deficiency results in a generally proinflammatory state; mice with genetically induced ST6Gal-1 deficiency exhibit exaggerated acute peritonitis and Th2 pulmonary inflammation (11,12). This phenotype was attributed specifically to the inactivation of the liver-specific promoter P1, one of six promoters regulating tissue-and cell-specific transcription of the ST6Gal-1 gene (13)(14)(15).…”

Section: Large-dose Intravenous Immunoglobulin (Ivig)mentioning

confidence: 99%

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Anti-inflammatory IgG Production Requires Functional P1 Promoter in β-Galactoside α2,6-Sialyltransferase 1 (ST6Gal-1) Gene

Jones

Nasirikenari

Lugade

et al. 2012

Journal of Biological Chemistry

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Background: ␤-Galactoside ␣2,6-sialyltransferase 1 (ST6Gal-1) action is essential for the anti-inflammatory activity in intravenous immunoglobulin (IVIG) therapy. Results: Fc sialylation changes in accordance to the severity of inflammation. Inactivation of the P1 promoter abrogated IgG Fc sialylation. Conclusion: Fc sialylation depends on ST6Gal-1 in the circulation. Defective Fc sialylation is a mechanism for the generally proinflammatory tendencies of the P1-ablated mutant mouse (Siat1⌬P1). Significance: Anti-inflammatory bioactivity of IVIG requires sialylated Fc.

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Section: Discussionmentioning

confidence: 99%

Section: Large-dose Intravenous Immunoglobulin (Ivig)mentioning

confidence: 99%

Anti-inflammatory IgG Production Requires Functional P1 Promoter in β-Galactoside α2,6-Sialyltransferase 1 (ST6Gal-1) Gene

Jones

Nasirikenari

Lugade

et al. 2012

Journal of Biological Chemistry

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“…The humoral response (28 -30), maintenance of myeloid homeostatic balance (22), modulation of dendritic cell activity (31), T cell functionality (32), and integrin signaling (33)(34)(35) are but a few physiologic processes with implicated ST6Gal-1 participation. The idea of ST6Gal-1 pleiotropy Expression of (top left) total ST6Gal-1 mRNA, (top right) P1-transcribedST6Gal-1 mRNA that contains the unique Exon H sequence (2), and (bottom) selected hepatic sialyltransferases were measured by real-time PCR relative to the expression of RPL32, a ribosomal protein, as a reference standard.…”

Section: Discussionmentioning

confidence: 99%

“…poiesis, as mice with a specific ablation to the P1 region had excessive neutrophilic and eosinophilic inflammatory responses (22,23). Siat1⌬P1 animals had the identical degree of excessive inflammation as Siat1-null animals that were completely devoid of ST6Gal-1, indicating only the P1-mediated pool of ST6Gal-1 was important for myelopoietic regulation.…”

mentioning

confidence: 95%

“…Siat1⌬P1 animals had the identical degree of excessive inflammation as Siat1-null animals that were completely devoid of ST6Gal-1, indicating only the P1-mediated pool of ST6Gal-1 was important for myelopoietic regulation. Because P1 transcriptional activity was not detected in the bone marrow (22), the data implicated the control of myelopoiesis by ST6Gal-1 produced by an extramedullary source, presumably the liver. To establish the link between hepatically expressed ST6Gal-1 and the myelopoietic events occurring in the bone marrow, we re-examined the biochemical consequence of ST6Gal-1 deficiency in the liver, particularly in relation to its role in the proper sialylation of serum glycoproteins.…”

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confidence: 96%

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Role for Hepatic and Circulatory ST6Gal-1 Sialyltransferase in Regulating Myelopoiesis

Jones

Nasirikenari

et al. 2010

Journal of Biological Chemistry

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Recent findings have established a role for the ST6Gal-1 sialyltransferase in modulating inflammatory cell production during Th1 and Th2 responses. ST6Gal-1 synthesizes the Sia(␣2,6) to Gal(␤1,4)GlcNAc linkage on glycoproteins on cell surfaces and in systemic circulation. Engagement of P1, one of six promoter/regulatory regions driving murine ST6Gal-1 gene expression, generates the ST6Gal-1 for myelopoietic regulation. P1 utilization, however, is restricted to the liver and silent in hematopoietic cells. We considered the possibility that myelopoiesis is responsive to the sialylation of liver-derived circulatory glycoproteins, such that reduced ␣2,6-sialylation results in elevated myelopoiesis. However, 2-dimensional differential in gel electrophoresis (2D-DIGE) analysis disclosed only minimal alterations in the sialylation of sera glycoproteins of ST6Gal-1-deficient mice when compared with wild-type controls, either at baseline or during an acute phase response when the demand for sialylation is greatest. Furthermore, sera from ST6Gal-1-deficient animals did not enhance myelopoietic activity in ex vivo colony formation assays. Whereas there was only minimal consequence to the ␣2,6-sialylation of circulatory glycoproteins, ablation of the P1 promoter did result in strikingly depressed levels of ST6Gal-1 released into systemic circulation. Therefore, we considered the alternative possibility that myelopoiesis may be regulated not by the hepatic sialyl glycoproteins, but by the ST6Gal-1 that was released directly into circulation. Supporting this, ex vivo colony formation was notably attenuated upon introduction of physiologic levels of ST6Gal-1 into the culture medium. Our data support the idea that circulatory ST6Gal-1, mostly of hepatic origin, limits myelopoiesis by a mechanism independent of hepatic sialylation of serum glycoproteins.␣2,6-Sialic acid modification is a common feature of glycoproteins in systemic circulation, particularly those glycoproteins originating from the liver. The ␣2,6 attachment of sialic acid to Gal(␤1,4)GlcNAc termini of glycoproteins is mediated by the sialyltransferase ST6Gal-1. Mutant mice unable to express ST6Gal-1 are essentially devoid of ␣2,6-sialyl modifications, as evidenced by the lack of binding to the Sambucus nigra lectin (SNA) 2 that specifically recognizes these structures (1). Hepatic expression of ST6Gal-1 is principally driven by P1 (2, 3), one of six independently operative promoter regions regulating transcription of the ST6Gal-1 gene (4). Another promoter, P3, is responsible for low-level ST6Gal-1 expression in the liver (5). Increased expression of liver ST6Gal-1, mediated by the P1 promoter, has long been recognized to be an integral part of the acute phase response (APR) (6 -8), and it was generally believed that elevation of ST6Gal-1 was necessary to address the increased demand for sialylation of the acute phase proteins. The Siat1⌬P1 mouse, with a specific inactivation of P1 without compromising ST6Gal-1 gene expression from the remaining promoters, was ...

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Hyper α2,6‐Sialylation Promotes CD4⁺ T‐Cell Activation and Induces the Occurrence of Ulcerative Colitis

Fan,

Li,

Zhao

et al. 2023

Advanced Science

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Abstractα2,6‐sialylation, catalyzed by α2,6‐sialyltransferase (ST6GAL1), plays a pivotal role in immune responses. However, the role of ST6GAL1 in the pathogenesis of ulcerative colitis (UC) remains unknown. ST6GAL1 mRNA is highly expressed in UC tissues compared with the corresponding adjacent normal tissues, and α2,6‐sialylation is significantly increased in the colon tissues of patients with UC. The expression of ST6GAL1 and proinflammatory cytokines, such as interleukin (IL)‐2, IL‐6, IL‐17, and interferon‐gamma, is also increased. The number of CD4+ T cells increases in UC patients. St6gal1 gene knockout (St6gal1−/‐) rats are established by clustered regularly interspaced short palindromic repeats (CRISPR)‐associated gene knockout system. St6gal1 deficiency reduces the levels of pro‐inflammatory cytokines and alleviates colitis symptoms in UC model rats. Ablation of α2,6‐sialylation inhibits the transport of the TCR to lipid rafts and suppresses CD4+ T‐cell activation. The attenuation of TCR signaling downregulates the expression of NF‐κB in ST6GAL1‐/‐ CD4+ T‐cells. Moreover, NF‐κB could bind to the ST6GAL1 promoter to increase its transcription. Ablation of ST6GAL1 downregulates the expression of NF‐κB and reduces the production of proinflammatory cytokines to relieve UC pathogenesis, which is a potential novel target for the clinical treatment of UC.

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Altered granulopoietic profile and exaggerated acute neutrophilic inflammation in mice with targeted deficiency in the sialyltransferase ST6Gal I

Cited by 68 publications

References 59 publications

Anti-inflammatory IgG Production Requires Functional P1 Promoter in β-Galactoside α2,6-Sialyltransferase 1 (ST6Gal-1) Gene

Anti-inflammatory IgG Production Requires Functional P1 Promoter in β-Galactoside α2,6-Sialyltransferase 1 (ST6Gal-1) Gene

Role for Hepatic and Circulatory ST6Gal-1 Sialyltransferase in Regulating Myelopoiesis

Hyper α2,6‐Sialylation Promotes CD4⁺ T‐Cell Activation and Induces the Occurrence of Ulcerative Colitis

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Altered granulopoietic profile and exaggerated acute neutrophilic inflammation in mice with targeted deficiency in the sialyltransferase ST6Gal I

Cited by 68 publications

References 59 publications

Anti-inflammatory IgG Production Requires Functional P1 Promoter in β-Galactoside α2,6-Sialyltransferase 1 (ST6Gal-1) Gene

Anti-inflammatory IgG Production Requires Functional P1 Promoter in β-Galactoside α2,6-Sialyltransferase 1 (ST6Gal-1) Gene

Role for Hepatic and Circulatory ST6Gal-1 Sialyltransferase in Regulating Myelopoiesis

Hyper α2,6‐Sialylation Promotes CD4+ T‐Cell Activation and Induces the Occurrence of Ulcerative Colitis

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Hyper α2,6‐Sialylation Promotes CD4⁺ T‐Cell Activation and Induces the Occurrence of Ulcerative Colitis