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Cited by 268Proteoglycans and glycosaminoglycans researchProtease and Inhibitor MechanismsTGF-β signaling in diseases

Versican—A Critical Extracellular Matrix Regulator of Immunity and Inflammation

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Wight, Thomas N., Kang, Inkyung, Evanko, Stephen P., Harten, Ingrid A., Chang, Mary Y., Pearce, Oliver M. T., Allen, Carys E., Frevert, Charles W.·2020·Frontiers in Immunology
DOI 10.3389/fimmu.2020.00512PMC PMC7105702
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Abstract

The extracellular matrix (ECM) proteoglycan, versican increases along with other ECM versican binding molecules such as hyaluronan, tumor necrosis factor stimulated gene-6 (TSG-6), and inter alpha trypsin inhibitor (IαI) during inflammation in a number of different diseases such as cardiovascular and lung disease, autoimmune diseases, and several different cancers. These interactions form stable scaffolds which can act as "landing strips" for inflammatory cells as they invade tissue from the circulation. The increase in versican is often coincident with the invasion of leukocytes early in the inflammatory process. Versican interacts with inflammatory cells either indirectly via hyaluronan or directly via receptors such as CD44, P-selectin glycoprotein ligand-1 (PSGL-1), and toll-like receptors (TLRs) present on the surface of immune and non-immune cells. These interactions activate signaling pathways that promote the synthesis and secretion of inflammatory cytokines such as TNFα, IL-6, and NFκB. Versican also influences inflammation by interacting with a variety of growth factors and cytokines involved in regulating inflammation thereby influencing their bioavailability and bioactivity. Versican is produced by multiple cell types involved in the inflammatory process. Conditional total knockout of versican in a mouse model of lung inflammation demonstrated significant reduction in leukocyte invasion into the lung and reduced inflammatory cytokine expression. While versican produced by stromal cells tends to be pro-inflammatory, versican expressed by myeloid cells can create anti-inflammatory and immunosuppressive microenvironments. Inflammation in the tumor microenvironment often contains elevated levels of versican. Perturbing the accumulation of versican in tumors can inhibit inflammation and tumor progression in some cancers. Thus versican, as a component of the ECM impacts immunity and inflammation through regulating immune cell trafficking and activation. Versican is emerging as a potential target in the control of inflammation in a number of different diseases.

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  • ECM contains other immunogenic GAGs, such as versican and biglycan, which stay latent in intact ECM.

    “Likewise, ECM contains other immunogenic GAGs, such as versican and biglycan, which stay latent in intact ECM.”

    From Immunogenicity of decellularized extracellular matrix scaffolds: a bottleneck in tissue engineering and regenerative medicine (2023) · cites this paper as [112]

    The Versican section identifies versican as an ECM proteoglycan bearing glycosaminoglycan chains, and “Versican: A Component of the Inflammatory Response” discusses inflammatory activity of both versican and biglycan. But the paper calls them proteoglycans, not GAGs, and does not say they stay latent in intact ECM; “Versican: Interplay With Leukocytes” reports evidence that intact versican can enhance inflammatory-cell infiltration. No page numbers were provided in our copy. (LLM, conf=0.88)

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  • Upon ECM damage or elevated activity of proteases, versican and biglycan are released and stimulate TLRs to activate inflammatory responses mainly via the NF-кB pathway, enhancing M1 polarization of macrophages and adaptive immunity activation.

    “Upon ECM damage or elevated activity of the proteases, they are released and stimulate TLRs to activate inflammatory responses mainly via the NF-кB pathway, enhancing M1 polarization of macrophages and adaptive immunity activation [112].”

    From Immunogenicity of decellularized extracellular matrix scaffolds: a bottleneck in tissue engineering and regenerative medicine (2023) · cites this paper as [112]

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Cited by

Sorted by citations

Authors
Wight, T. N., Kang, I., Evanko, S. P., Harten, I. A., Chang, M. Y., Pearce, O. M. T., Allen, C. E., & Frevert, C. W.
Affiliations
  • Benaroya Research Institute (US)
  • University of Washington (US)
  • Queen Mary University of London (GB)
Corresponding author
Wight, Thomas N.
ORCID
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2020-03-24
Volume
11
Pages
512-512
ISSN
1664-3224 (ISSN-L)
DOI
10.3389/fimmu.2020.00512
PMC
PMC7105702
OpenAlex
W3013536489
Cited by
268
References
4
Citations by year
2026: 33 · 2025: 55 · 2024: 61 · 2023: 43 · 2022: 38 · 2021: 24 · 2020: 14
FWCI
3.46
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Immunology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Queen Mary Research Online (Queen Mary University of London) (submittedVersion, cc-by)
Funders
National Institutes of Health (DK 096087, AI 125378)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
Keywords
versican, extracellular matrix, inflammation, immunity, hyaluronic acid, TSG-6, inter-alpha-trypsin inhibitor, CD44, PSGL-1, Toll-like receptors, leukocyte migration, inflammatory cytokines, NF-κB signaling, tumor microenvironment, stromal cells, myeloid cells, anti-inflammatory microenvironment, lung inflammation
MeSH terms
Animals, Extracellular Matrix, Humans, Hyaluronic Acid, Inflammation, Leukocytes, Lipopolysaccharides, Rabbits, Receptors, Cell Surface, Lymphocyte Subsets, Stromal Cells, Myeloid Cells, Models, Animal, Toll-Like Receptors, Mice, Rats, Versicans

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