Sialyltransferase ST3Gal-IV controls CXCR2-mediated firm leukocyte arrest during inflammation

Frommhold, David; Ludwig, Andreas; Bixel, M. Gabriele; Zarbock, Alexander; Babushkina, I. V.; Weissinger, Melitta; Cauwenberghs, Sandra; Ellies, Lesley G.; Marth, Jamey D.; Beck‐Sickinger, Annette G.; Sixt, Michael; Lange-Sperandio, Bärbel; Zernecke, Alma; Brandt, Ernst; Weber, Christian; Vestweber, Dietmar; Ley, Klaus; Sperandio, Markus

doi:10.1084/jem.20070846

Cited by 71 publications

(70 citation statements)

References 42 publications

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“…This additional atheroprotective effect would not appear to be mediated through an increase in levels of alkaline phosphatase or vitamin B 12 . Sialylation of chemokines or their receptors can influence the recruitment of inflammatory cells to atherosclerotic plaques, [36][37][38] a finding that may be relevant to the atheroprotective effect of del12.…”

Section: Discussionmentioning

confidence: 99%

VariantASGR1Associated with a Reduced Risk of Coronary Artery Disease

et al. 2016

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BACKGROUNDSeveral sequence variants are known to have effects on serum levels of non-highdensity lipoprotein (HDL) cholesterol that alter the risk of coronary artery disease. METHODSWe sequenced the genomes of 2636 Icelanders and found variants that we then imputed into the genomes of approximately 398,000 Icelanders. We tested for association between these imputed variants and non-HDL cholesterol levels in 119,146 samples. We then performed replication testing in two populations of European descent. We assessed the effects of an implicated loss-of-function variant on the risk of coronary artery disease in 42,524 case patients and 249,414 controls from five European ancestry populations. An augmented set of genomes was screened for additional loss-of-function variants in a target gene. We evaluated the effect of an implicated variant on protein stability. RESULTSWe found a rare noncoding 12-base-pair (bp) deletion (del12) in intron 4 of ASGR1, which encodes a subunit of the asialoglycoprotein receptor, a lectin that plays a role in the homeostasis of circulating glycoproteins. The del12 mutation activates a cryptic splice site, leading to a frameshift mutation and a premature stop codon that renders a truncated protein prone to degradation. Heterozygous carriers of the mutation (1 in 120 persons in our study population) had a lower level of non-HDL cholesterol than noncarriers, a difference of 15.3 mg per deciliter (0.40 mmol per liter) (P = 1.0×10 −16 ), and a lower risk of coronary artery disease (by 34%; 95% confidence interval, 21 to 45; P = 4.0×10 −6 ). In a larger set of sequenced samples from Icelanders, we found another loss-of-function ASGR1 variant (p.W158X, carried by 1 in 1850 persons) that was also associated with lower levels of non-HDL cholesterol (P = 1.8×10 −3 ). CONCLUSIONSASGR1 haploinsufficiency was associated with reduced levels of non-HDL cholesterol and a reduced risk of coronary artery disease. (Funded by the National Institutes of Health and others.)A BS TR AC T

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Section: Discussionmentioning

confidence: 99%

VariantASGR1Associated with a Reduced Risk of Coronary Artery Disease

et al. 2016

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“…47 Microvascular and hemodynamic parameters did not vary significantly between the treatment groups (see Supplemental Table S3 at http://ajp.amjpathol.org). Depending on the time of Figure 3.…”

Section: Leukocyte Recruitment During Trauma-induced Inflammation Of mentioning

confidence: 99%

Protein C Concentrate Controls Leukocyte Recruitment during Inflammation and Improves Survival during Endotoxemia after Efficient in Vivo Activation

Frommhold

Tschada

Braach

et al. 2011

The American Journal of Pathology

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Anti-inflammatory properties of protein C (PC) concentrate are poorly studied compared to activated protein C, although PC is suggested to be safer in clinical use. We investigated how PC interferes with the leukocyte recruitment cascade during acute inflammation and its efficacy during murine endotoxemia. We found that similar to activated protein infusion, intravenous PC application reduced leukocyte recruitment in inflamed tissues in a dose-and timedependent manner. During both tumor necrosis factor-␣ induced and trauma-induced inflammation of the cremaster muscle, intravital microscopy revealed that leukocyte adhesion and transmigration, but not rolling, were profoundly inhibited by 100 U/kg PC. Moreover, PC blocked leukocyte emigration into the bronchoalveolar space during lipopolysaccharide (LPS) induced acute lung injury. PC was efficiently activated in a murine endotoxemia model, which reduced leukocyte infiltration of organs and strongly improved survival (75% versus 25% of control mice). Dependent on the inflammatory model, PC provoked a significant inhibition of leukocyte recruitment as early as 1 hour after administration. PC-induced inhibition of leukocyte recruitment during acute inflammation critically involves thrombomodulin-mediated PC activation, subsequent endothelial PC receptor and protease-activated receptor-1-dependent signaling, and down-regulation of intercellular adhesion molecule 1 leading to reduced endothelial inflammatory response. We conclude that during acute inflammation and sepsis, PC is a fast acting and effective therapeutic approach to block leukocyte recruitment and improve survival.

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“…That said, it remains to be determined whether ST3Gal-4 is also a critical regulator of selectin-mediated adhesion for other human nonmyeloid cell types. Also, the disruption of ST3Gal-4 activity in humans may perturb additional pathways that have been shown to be modified in ST3Gal-4 2/2 mice, like CXCR2-dependent activation, 49 and von Willebrand factor and platelet circulation half-life. 50 Finally, the remarkable species-specific function of the glycosyltransferases suggests the possibility that evolutionary divergence may have conditioned human immunity.…”

Section: E-selectin-mediated Human Leukocyte Adhesionmentioning

confidence: 99%

ST3Gal-4 is the primary sialyltransferase regulating the synthesis of E-, P-, and L-selectin ligands on human myeloid leukocytes

Mondal

Buffone

Stolfa

et al. 2015

Blood

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• A single a(2,3) sialyltransferase, ST3Gal-4, controls sLe X biosynthesis on N-and O-glycans in cells of human myeloid lineage.• Blocking this enzyme activity prevents human neutrophil adhesion to E-, P-, and L-selectin.The precise glycosyltransferase enzymes that mediate selectin-ligand biosynthesis in human leukocytes are unknown. This knowledge is important because selectin-mediated cell tethering and rolling is a critical component of both normal immune response and various vascular disorders. We evaluated the role of 3 a(2,3)sialyltransferases, ST3Gal-3, -4, and -6, which act on the type II N-Acetyllactosamine structure (Galb1,4GlcNAc) to create sialyl Lewis-X (sLe X ) and related sialofucosylated glycans on human leukocytes of myeloid lineage. These genes were either silenced using lentiviral short hairpin RNA (shRNA) or functionally ablated using the clustered regularly interspaced short palindromic repeat/ Cas9 technology. The results show that ST3Gal-4, but not ST3Gal-3 or -6, is the major sialyltransferase regulating the biosynthesis of E-, P-, and L-selectin ligands in humans. Reduction in ST3Gal-4 activity lowered cell-surface HECA-452 epitope expression by 75% to 95%. Glycomics profiling of knockouts demonstrate an almost complete loss of the sLe X epitope on both leukocyte N-and O-glycans. In cell-adhesion studies, ST3Gal-4 knockdown/knockout cells displayed 90% to 100% reduction in tethering and rolling density on all selectins. ST3Gal-4 silencing in neutrophils derived from human CD34 1 hematopoietic stem cells also resulted in 80% to 90% reduction in cell adhesion to all selectins. Overall, a single sialyltransferase regulates selectin-ligand biosynthesis in human leukocytes, unlike mice where multiple enzymes contribute to this function. (Blood. 2015;125(4):687-696)

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Sialyltransferase ST3Gal-IV controls CXCR2-mediated firm leukocyte arrest during inflammation

Cited by 71 publications

References 42 publications

VariantASGR1Associated with a Reduced Risk of Coronary Artery Disease

VariantASGR1Associated with a Reduced Risk of Coronary Artery Disease

Protein C Concentrate Controls Leukocyte Recruitment during Inflammation and Improves Survival during Endotoxemia after Efficient in Vivo Activation

ST3Gal-4 is the primary sialyltransferase regulating the synthesis of E-, P-, and L-selectin ligands on human myeloid leukocytes

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