Decreased erythrocyte binding of Siglec-9 increases neutrophil activation in sickle cell disease

Zachary M. Kiser, Anel Lizcano, Julia Nguyen, Greta L. Becker, John D. Belcher, Ajit P. Varki, Gregory M. Vercellotti

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Oxidative stress and inflammation promote vaso-occlusion in sickle cell disease (SCD). CD33-related Sialic acid-binding immunoglobulin-type lectins (CD33rSiglecs) are cell surface proteins that recognize sialic acids inhibit innate immune cell functions. We have shown that Siglec-9 on human neutrophils interact with erythrocyte sialic acids (prominently glycophorin-A (GYPA) to suppress neutrophil reactive oxygen species (ROS). We hypothesized that altered sickle erythrocyte membrane sialic acid leads to decreased Siglec-9 binding capability, and thus a decreased neutrophil oxidative burst. SS erythrocytes express significantly more sialic acid than AA erythrocytes (p = 0.02). SS erythrocytes displayed significantly less Siglec-9-Fc binding 39% ± 11 (mean ± SEM) compared to AA erythrocytes 78% ± 5 (p = 0.009). Treatment of AA erythrocytes with sialidase to remove sialic acid decreased binding to 3% ± 7.9 (p ≤ 0.001). When freshly isolated neutrophils were incubated with AA erythrocytes, neutrophils achieved 16% ± 6 of the oxidative burst exhibited by a stimulated neutrophil without erythrocytes. In contrast, neutrophils incubated with SS erythrocytes achieved 47% ± 6 of the oxidative burst (AA versus SS, p = 0.03). Stimulated neutrophils incubated with AA erythrocytes showed minimal NET formation while with SS erythrocytes NETs increased. SS erythrocytes are deficient in binding to neutrophil Siglec-9 which may contribute to the increased oxidative stress in SCD.

Original languageEnglish (US)
Article number102399
JournalBlood Cells, Molecules, and Diseases
Volume81
DOIs
StatePublished - Mar 2020

Bibliographical note

Funding Information:
Dr. Kiser was supported by the Hematology Research Training Grant T32 HL007062/HL/NHLBI . This research was supported by National Institutes of Health grants 5R01HL114567 and RO1GM3273 (AV).

Publisher Copyright:
© 2019 Elsevier Inc.

Keywords

  • Oxidative stress
  • Sialic acid
  • Sickle cell disease
  • Siglec-9

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural

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