Sulphated and Non-sulphated Disaccharides: Cellular And Molecular Mechanisms of Action in Macrophage Function

PhD Thesis


Bajwa, P. 2022. Sulphated and Non-sulphated Disaccharides: Cellular And Molecular Mechanisms of Action in Macrophage Function. PhD Thesis University of East London School of Health, Sport and Bioscience https://doi.org/10.15123/uel.8qw37
AuthorsBajwa, P.
TypePhD Thesis
Abstract

Sulphated disaccharides are degradation products of heparinase that are released by inflammatory cells at sites of inflammation. Recent studies have shown that heparin derived sulphated disaccharides inhibit macrophage TNF-α synthesis, delayed-type hypersensitivity, rat adjuvant and rat and mouse collagen induced arthritis, with indications that they act on T-cell and macrophage function. The mechanisms by which these occur are unknown. Therefore, this study aims to investigate the mechanism of action of sulphated disaccharides through which they produce an inhibitory effect. In this study, the impact of sulphated disaccharides was tested on monocyte-macrophage functions in vitro.
In this study, it was established that sulphated disaccharides inhibit PMAstimulated macrophage-like cell differentiation (10⁻¹¹ – 10⁻⁴ M). The reduced numbers of adherent macrophages cells leads to the reduction of proinflammatory macrophages. Inhibition of phosphorylation of p38 and ERK1/2 was found and was directly proportional to sulphated disaccharide structural features, namely selective (HDS-I, HDS-III) or oligosulphation (SOS, DOS). Preincubation of monocytes with sulphated disaccharides inhibited PMA-induced calcium mobilisation. In addition, this study demonstrated that treatment with sulphated disaccharides induces a phenotypic switch of differentiated macrophages into an anti-inflammatory phenotype and also the pro-inflammatory phenotype into an anti-inflammatory phenotype.
The current study provides an insight into the possibility of targeting inhibition of monocyte-macrophage-differentiation through inhibition of calcium mobilisation, leading to de-activation of p38 and ERK1/2 MAPK, TNF-α production, and ultimately inhibition of cell-differentiation induced cell surface adhesion molecule expression. In addition, sulphated disaccharides promote macrophage divergence towards an anti-inflammatory phenotype. The findings of this study indicate that sulphate disaccharides exhibit their inhibitory action even at very low concentrations, especially the oligosulphated compounds. Thus, suggesting a novel molecular mechanism for the treatment of macrophage-dependent chronic inflammatory diseases.

Year2022
PublisherUniversity of East London
Digital Object Identifier (DOI)https://doi.org/10.15123/uel.8qw37
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Publication dates
Online04 Jul 2022
Publication process dates
Submitted24 Jun 2022
Deposited04 Jul 2022
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