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Review
. 2023 Feb 14:10:1146685.
doi: 10.3389/fmolb.2023.1146685. eCollection 2023.

Heparan sulfates and heparan sulfate binding proteins in sepsis

Affiliations
Review

Heparan sulfates and heparan sulfate binding proteins in sepsis

Yi-En Liao et al. Front Mol Biosci. .

Abstract

Heparan sulfates (HSs) are the main components in the glycocalyx which covers endothelial cells and modulates vascular homeostasis through interactions with multiple Heparan sulfate binding proteins (HSBPs). During sepsis, heparanase increases and induces HS shedding. The process causes glycocalyx degradation, exacerbating inflammation and coagulation in sepsis. The circulating heparan sulfate fragments may serve as a host defense system by neutralizing dysregulated Heparan sulfate binding proteins or pro-inflammatory molecules in certain circumstances. Understanding heparan sulfates and heparan sulfate binding proteins in health and sepsis is critical to decipher the dysregulated host response in sepsis and advance drug development. In this review, we will overview the current understanding of HS in glycocalyx under septic condition and the dysfunctional heparan sulfate binding proteins as potential drug targets, particularly, high mobility group box 1 (HMGB1) and histones. Moreover, several drug candidates based on heparan sulfates or related to heparan sulfates, such as heparanase inhibitors or heparin-binding protein (HBP), will be discussed regarding their recent advances. By applying chemical or chemoenzymatic approaches, the structure-function relationship between heparan sulfates and heparan sulfate binding proteins is recently revealed with structurally defined heparan sulfates. Such homogenous heparan sulfates may further facilitate the investigation of the role of heparan sulfates in sepsis and the development of carbohydrate-based therapy.

Keywords: HMGB1 (high mobility group box 1); heparan sulfate; heparan sulfate binding proteins; heparin; histones.

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Conflict of interest statement

JL is a founder and chief scientific officer for Glycan Therapeutics. KA is a principal scientist at Glycan Therapeutics. The JL lab at UNC has received a gift from Glycan Therapeutics to support research in glycoscience. Y-EL declare no competing interests.

Figures

FIGURE 1
FIGURE 1
HSs and HSBPs on glycocalyx in health and sepsis. (A) Heparan sulfates (HSs) present on the cell surfaces as proteoglycans, binding to perlecan, syndecans-1, and glypican. With other glycoproteins, including chondroitin sulfate (Tam et al., 2008) and hyaluronan (HA) bound to syndecans-1 and CD44, HS proteoglycans form the glycocalyx and regulate cell signaling by interacting with HS binding proteins (HSBPs) such as fibroblast growth factor receptor (FGFR), intracellular adhesion molecule-1 (iCAM-1). Binding to HSBPs requires specific HS structures; for example, FGFR binding requires 6-O-sulfated glucosamine and more than ten saccharide units. (B) During sepsis, HSs are released by upregulated heparanase. HSs mediate inflammation by binding to dysregulated HSBPs, such as extracellular histones, high mobility group box 1 (HMGB1), and interleukin 8 (IL-8). HSs also serve as co-receptors for immune cells by binding to p-selectin. Specific sulfation and length are also required for HS binding to heparanase and HMGB1.
FIGURE 2
FIGURE 2
HMGB1 damage and proposed anti-HMGB1 mechanism of HSs in sepsis. (A) Infection sources, such as bacterial products, induce HMGB1 to be released from immune cells or damaged cells. HMGB1 binds to toll-like receptor 4 (TLR4) and receptor for advanced glycation end products (RAGE) on neutrophils and macrophages, inducing neutrophil extracellular trap (NET) formation and cytokines/chemokines release. HMGB1 also forms a complex with lipopolysaccharide (LPS), binding to RAGE on host cells and inducing cell pyroptosis. In addition, LPS forms a complex with apolipoprotein A-I (apoA-I), which can transport to the liver for clearance. (B) HSs reduce HMGB1-induced inflammation by inhibiting HMGB1/LPS complex binding to RAGE. Also, HSs facilitate apoA-I/LPS complex formation, replacing the LPS/HMGB1 complex. HSs are also proposed to reduce HMGB1/LPS complex formation and inhibit HMGB1/RAGE signaling in sepsis, yet the proposed mechanisms need further validation.
FIGURE 3
FIGURE 3
The structure of octadecassacharide (18-mer). The octadeacassacharide (18-mer) is produced by chemoenzymatic synthesis (Liao et al., 2023).
FIGURE 4
FIGURE 4
Histone damage and proposed anti-histone mechanism of HSs in sepsis. (A) Histones are released from activated neutrophils, macrophages, and damaged host cells during sepsis. Specifically, citrullinated histone 3 (CitH3) can be used as a NET marker. Extracellular histones directly interrupt cell integrity by interacting with cell membranes and inducing calcium influx, causing cell death. Histones also bind to TLR2/4 on macrophages and platelets, inducing cytokine release or coagulation. (B) HSs reduce histone-induced inflammation and coagulation by directly neutralizing histones, inhibiting their interactions with cell membranes and TLR2/4 on macrophages and platelets.
FIGURE 5
FIGURE 5
Structures of heparins. (A) Unfractionated heparin (UFH) and UFH derivatives, including low molecular weight heparin (LMWH), N-acetyl heparin, 2-O, 3-O-desulfated heparin (ODSH), and SST0001 are comprised of repeating disaccharide units. Glucosamine-glucuronic acid is more abundant that glucosamine-iduronic acid. Sulfation sites are varied as indicated. (B) The pentasaccharide binds to antithrombin III (AT III). The sequence is present in UFH and LMWH. (C,D,F) The structure of non-anticoagulant heparins. (C) The pentasaccharide in N-acetyl heparin. N-acetyl glucosamine eliminate anticoagulant activity. (D) The pentasaccharide in ODSH greatly reduces anticoagulant activity. (E) The structure of fondaparinux. (F) The pentasaccharide in SST0001 does not have anticoagulant activity.

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