Effects of α1‐acid Glycoprotein Fucosylation on its Ca²⁺ Mobilizing Capacity in Neutrophils

Abstract

We recently showed that the acute‐phase protein α1‐acid glycoprotein (AGP) induces rises in cytosolic calcium concentration, [Ca2+]i, in neutrophils through sialic acid dependent interactions with the neutrophil receptors siglec‐5 and/or siglec‐14. Whereas both siglec‐5 and siglec‐14 have a relatively broad specificity for sialylated oligosaccharide structures, including both structures with terminal α2–3 or α2–6 linked sialic acid, there is a markedly reduced affinity to the fucosylated epitope sialyl Lewis x (SLex). Increased fucosylation, leading to increased expression of SLex on AGP is commonly associated with inflammatory conditions. In the present study, we investigated whether an increased SLex expression would affect the Ca2+‐mobilizing effect of AGP. AGP with elevated fucose content isolated from patients with untreated chronic joint inflammation showed a decreased [Ca2+]i modulatory effect on neutrophils compared to normally fucosylated AGP. Furthermore a hyperfucosylated AGP form produced by in vitro fucosylation, that consequently had an elevated expression of SLex, could not elicit a [Ca2+]i increase in neutrophils. The role of the carbohydrate portion of AGP in modulating neutrophil responses was further strengthened by showing that synthetic glycoconjugates carrying oligosaccharides with terminal α2–3 or α2–6 linked sialic acid were able to mimic the Ca2+‐mobilizing effect of AGP whereas a synthetic glycoconjugate carrying SLex was not. Based on these data, we conclude that increased fucosylation can alter the ability of AGP to induce neutrophil signalling and further supports an important role of the oligosaccharide chains of AGP in the modulation of leukocyte functions during an inflammatory process.

Differential glycosylation of alpha-1-acid glycoprotein (AGP-1) contributes to its functional diversity

“…To define this, we first defined relevant functions for AGP-1 in the inflammatory system. AGP-1-induces Ca 2+ influx in neutrophils (35,36) to activate these cells (24). In accordance with our previous data, sAGP-1-induces concentration-dependent activation of neutrophil adhesion and migration.…”

Regulatory insights into the production of UDP-N-acetylglucosamine by Lactobacillus casei

“…They are also used as anchoring molecules for pathogens, antibodies and hormones. [1][2][3][4] The synthesis of those carbohydrates is catalyzed by glycosyltransferases that use activated sugars, such…”

Fucosylated Glycans in α1-Acid Glycoprotein for Monitoring Treatment Outcomes and Prognosis of Cancer Patients

“…Generally, AGP has highly glycosylated N -glycan chains on the molecule with more than 45% content and with abundant heterogeneity. It has therefore been demonstrated that despite expression of different genomic variants and mRNA levels of AGP, drastic changes occur frequently in not only serum concentrations but also their glycan structures including branching, sialylation and, in particular, fucosylation degrees as posttranslational modification involving in rapid responses to various biological phenomena [ 25 – 35 , 78 – 84 ]. It was also shown that each AGP glycoform was renewed at a rate of 15% per day of the plasma pool [ 85 ].…”