The proteoglycan glycomatrix: A sugar microenvironment essential for complement regulation
Open accessAbstract
Proteoglycans (PGs) are major components of all mammalian tissues, being present ubiquitously on cell surfaces and within extracellular matrices (ECM). They play vital roles in mammalian physiology and have been implicated in many disease processes. PGs comprise a single core protein with one or more glycosaminoglycan (GAG) chains attached where these un-branched polysaccharides are composed of repeating disaccharide units that show considerable diversity in their disaccharide composition, glycosidic linkages, and levels/positions of sulfation (1, 2). GAGs, therefore, contain huge numbers of structural permutations (even in the same chain), representing a vast possible array of diverse structures that can determine the fate of local environments (3): i.e., through their modulation of protein-binding and activity. Thus, PGs constitute a tissue and region-specific microenvironment of sugar molecules, both within the ECM and at the cell-matrix interface, which acts as a local regulator of tissue function and homeostasis. As described below, it is our opinion that this proteoglycan "glycomatrix" plays a key role in the regulation of the immune system by acting as a molecular postcode that controls local immune function (4). Here we will illustrate this with examples of the effects of PGs/GAGs on the immune system in the eye, heart, kidney, and lung. In particular, we will focus on recent evidence that GAGs can positively and negatively regulate the alternative pathway of complement and suggest how the dysregulation of this aspect of innate immunity may contribute to disease processes in a tissue-specific manner. © 2013 Clark, Bishop and Day.
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The inability of C3a to pass through BrM may reflect its higher positive net charge at neutral pH, causing it to be trapped within the negatively charged BrM due to glycosaminoglycans.
“This observation may reflect the higher positive net charge of C3a at neutral pH [35], causing it to be trapped within the BrM, which is negatively charged due to the presence of glycosaminoglycans [35,37,38].”
From Bruch’s Membrane: A Key Consideration with Complement-Based Therapies for Age-Related Macular Degeneration (2023) · cites this paper as [38]
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Heparan Sulfate ProteoglycansPreprint
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- Authors
- Clark, S. J., Bishop, P. N., & Day, A. J.
- Affiliations
- University of Manchester (GB)
- Wellcome Centre for Cell-Matrix Research (GB)
- Corresponding author
- Day, Anthony J.
- Venue
- Frontiers in Immunology
- Publisher
- Frontiers Media SA
- Published
- 2013
- Volume
- 4
- Pages
- 412-412
- ISSN
- 1664-3224 (ISSN-L)
- PMC
- PMC3840399
- OpenAlex
- W2138010437
- Cited by
- 39
- References
- 30
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 7 · 2023: 2 · 2022: 3 · 2021: 1 · 2020: 1 · 2019: 2 · 2018: 4 · 2017: 3 · 2016: 2 · 2015: 5 · 2014: 5
- FWCI
- 2.32
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Frontiers in Immunology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Medical Research Council (MR/K024418/1, MR/K004441/1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
- Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
- Keywords
- proteoglycans, glycosaminoglycans, complement regulation, alternative complement pathway, extracellular matrix, innate immunity, immune regulation, sulfation, disaccharide composition, eye, heart, kidney, lung
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