Sialic acid in the regulation of blood cell production, differentiation and turnover

Abstract

Sialic acid is a unique sugar moiety that resides in the distal and most accessible position of the glycans on mammalian cell surface and extracellular glycoproteins and glycolipids. The potential for sialic acid to obscure underlying structures has long been postulated, but the means by which such structural changes directly affect biological processes continues to be elucidated. Here, we appraise the growing body of literature detailing the importance of sialic acid for the generation, differentiation, function and death of haematopoietic cells. We conclude that sialylation is a critical post-translational modification utilized in haematopoiesis to meet the dynamic needs of the organism by enforcing rapid changes in availability of lineage-specific cell types. Though long thought to be generated only cell-autonomously within the intracellular ER-Golgi secretory apparatus, emerging data also demonstrate previously unexpected diversity in the mechanisms of sialylation. Emphasis is afforded to the mechanism of extrinsic sialylation, whereby extracellular enzymes remodel cell surface and extracellular glycans, supported by charged sugar donor molecules from activated platelets.

Keywords: bone marrow; cell death; extrinsic sialylation; galactose; galectin; haematopoiesis; lectins; sialic acid; sialyltransferase; siglec.

Fig 1.. Modes of sialylation.

Sialic acid is synthesized in the cytosol from glycolytic precursors, then conjugated to cytidine triphosphate (CTP) to form CMP-Sialic acid, the charged sugar donor substrate that participates in sialylation reactions. The secretory pathway involves progressive remodeling of glycans attached to glycoproteins or glycolipids as they transit through the endoplasmic reticulum and Golgi apparatus. Intrinsic sialylation of a terminally galactosylated structure occurs in the trans-Golgi, after which glycoconjugates are typically transported to be embedded in the membrane or exported. Extrinsic sialylation differs in that extracellular sialyltransferases catalyze sialylation of secreted or cell surface glycans, independently of the ER-Golgi pathway. The relationship between the cell producing the sialyltransferase and the target cell can vary, as illustrated by autocrine (self-sialylation by secreted enzyme), paracrine (sialylation of a tissue by localized enzyme secretion), or endocrine (sialylation of distant targets after transport in the blood). Emerging evidence suggests that extracellular sialyltransferase can also be imported into recipient cells and utilized in intracellular reactions.

Fig 2.. Diverse functions of sialic acid in hematopoietic cells.

(A) Hematopoietic cells accrue sialic acid during early development, but rapidly shed their sialic acid when activated or in response to inflammatory stimuli. This desialylation rapidly generates pro-inflammatory granulocytes and macrophages, prepares dendritic cells for antigen presentation, and accelerates the senescence and turnover of platelets and erythrocytes. (B) Exposure to LPS and TNF-α in macrophages prompts rapid desialylation of the crucial cell surface receptors TLR4 and TNFR, activating a positive feedback loop of inflammation that promotes M1 differentiation but ultimately limits macrophage lifespan. (C) Macrophages and granulocytes express cell surface Siglecs to sense environmental sialic acid. Growth factors M-CSF and GM-CSF stimulate monocyte Siglec-7 and Siglec-9 expression, which sense tissue sialic acid ligands to promote PD-L1 and IL-10 expression, M2 differentiation, and cell death. (D) On neutrophils, Siglec-9 engages erythrocyte sialic acids to inhibit ROS production, NETosis, antimicrobial functions, and promote inflammatory cell death. (E) Lymphocytes possess abundant sialic acid, which in B cells plays a critical role in meeting developmental milestones via engagement of Siglec-2/CD22. Mature B and T cells rapidly lose sialic acid upon activation, exposing underlying galactose for galectin activation. In B cells, desialylation limits BCR signaling and allows for galectin engagement, which directs differentiation into memory or plasma cell phenotypes. In T cells, desialylation allows for robust cytotoxic cell activation but also promotes cell death. Galectin engagement further influences differentiation into specific helper T cell subtypes.