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

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

doi:10.1016/j.bcmd.2019.102399

Cited by 15 publications

(7 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In SCD, erythrocytes rapidly age, losing membrane elasticity and undergoing changes in cell membrane composition and protein expression. SCD-erythrocytes contain more SA compared to healthy erythrocytes but show lowered binding with neutrophil-Siglec-9 ( 59 ). Consequently, culturing healthy neutrophils with SCD erythrocytes leads to increased ROS release due to lowered Siglec-9 activation.…”

Section: Introductionmentioning

confidence: 99%

Siglecs Modulate Activities of Immune Cells Through Positive and Negative Regulation of ROS Generation

2021

View full text Add to dashboard Cite

Reactive oxygen species (ROS) are a group of oxygen-containing highly-reactive molecules produced from oxidative metabolic processes or in response to intracellular signals like cytokines and external stimuli like pathogen attack. They regulate a range of physiological processes and are involved in innate immune responses against infectious agents. Deregulation of ROS contributes to a plethora of disease conditions. Sialic acids are carbohydrates, present on cell surfaces or soluble proteins. Sialic acid-binding immunoglobulin-like lectins (Siglecs) recognize and bind to sialic acids. These are widely expressed on various types of immune cells. Siglecs modulate immune activation and can promote or inhibit ROS generation under different contexts. Siglecs promote ROS-dependent cell death in neutrophils and eosinophils while limiting oxidative stress associated with chronic obstructive pulmonary disease (COPD), sickle cell disease (SCD), coronavirus disease-2019 (COVID-19), etc. This review distinguishes itself in summarizing the current understanding of the role of Siglecs in moderating ROS production and their distinct effect on different immune cells; that ultimately determine the cellular response and the disease outcome. This is an important field of investigation having scope for both expansion and medical importance.

show abstract

Section: Introductionmentioning

confidence: 99%

Siglecs Modulate Activities of Immune Cells Through Positive and Negative Regulation of ROS Generation

2021

View full text Add to dashboard Cite

show abstract

“…Furthermore, lysate prepared from both AARBCs and SSRBCs did not enhance adhesion of normal neutrophils to HUVECs. Instead, as we have previously shown with monocytoid leukocytes, 13 it is possible that known properties of SSRBCs, including activated adhesion receptors, membrane phosphatidylserine exposure or altered sialic acid expression, 14 contribute to neutrophil activation. Ultimately, it is important to more thoroughly investigate and understand the mechanism by which SSRBCs activate neutrophils and to delineate the full extent of SSRBCs effects on neutrophil activation, as well as the contribution of specific SSRBC subpopulations.…”

Section: Sickle Red Blood Cells Directly Activate Neutrophilsmentioning

confidence: 86%

Sickle red blood cells directly activate neutrophils

Lee,

Batchvarova,

Delahunty

et al. 2024

Br J Haematol

View full text Add to dashboard Cite

“… 29 These findings are also consistent with those of Kiser et al, who showed that RBCs from patients with SCD had decreased Siglec-9 binding, whereas the availability of sialic acid on the RBC surface was increased compared with healthy control RBCs. 30 , 31 However, data from Aminoff and Ekeke showed decreased GPA/sialic acid content in RBCs from patients with SCD compared with HS. 32 , 33 Thus, further investigations of the structural alterations of GPA and/or its sialic acid surface content are required to determine the RBC ability to interact with immune cells.…”

Section: Discussionmentioning

confidence: 98%

Aberrant GPA expression and regulatory function of red blood cells in sickle cell disease

Marshall,

Klein,

Karki

et al. 2024

Blood Advances

View full text Add to dashboard Cite

Glycophorin A (GPA), a red blood cell (RBC) surface glycoprotein, can maintain peripheral blood leukocyte quiescence through interaction with a sialic acid-binding Ig-like lectin (Siglec-9). Under inflammatory conditions such as sickle cell disease (SCD), RBCs' GPA undergo structural changes affecting this interaction. Peripheral blood samples from SCD patients pre- and post-RBC transfusion were probed for neutrophil and monocyte activation markers and analyzed by FACS; RBCs were purified and tested by FACS for Siglec-9 binding and GPA expression, and incubated ex vivo with cultured endothelial cells to evaluate their effect on barrier function. Activated leukocytes from healthy subjects (HS) were co-incubated with healthy RBCs (RBCH), with GPA-altered RBCs, or with GPA-overexpressing (OE) cells, and analyzed by FACS. Monocyte CD63 and neutrophil CD66b from SCD patients at baseline were increased 47% and 27%, respectively, as compared to HS (p=0.0017, p=0.0162). Post-transfusion, these markers were suppressed by 22% and 17% (p=0.0084, p=0.0633), respectively. GPA expression on RBCSCD was 38% higher (p=0.0291) with decreased Siglec-9 binding compared to RBCH (0.0266). Monocyte CD63 and neutrophil CD66b was suppressed by 26% and 10%, respectively, following incubation with RBCH, (p=0.0464, p=0.0388) and GPA-OE cells, but not with GPA-altered RBCs. Endothelial barrier dysfunction following LPS challenge was restored fully with exposure to RBCH, but not with RBCSCD from patients in pain crisis, nor with RBCH with altered GPA. In conclusion, RBCSCD, prior to transfusion, do not effectively maintain the quiescence of leukocytes and endothelium, but quiescence is restored through RBC transfusion likely by re-established GPA-Siglec-9 interactions.

show abstract

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

Cited by 15 publications

References 30 publications

Siglecs Modulate Activities of Immune Cells Through Positive and Negative Regulation of ROS Generation

Siglecs Modulate Activities of Immune Cells Through Positive and Negative Regulation of ROS Generation

Sickle red blood cells directly activate neutrophils

Aberrant GPA expression and regulatory function of red blood cells in sickle cell disease

Contact Info

Product

Resources

About