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Immunomodulatory Role of the Extracellular Matrix Within the Liver Disease Microenvironment
Open accessAbstract
Chronic liver disease when accompanied by underlying fibrosis, is characterised by an accumulation of extracellular matrix (ECM) proteins and chronic inflammation. Although traditionally considered as a passive and largely architectural structure, the ECM is now being recognised as a source of potent DAMPs with immune-active peptides and domains. In parallel, the ECM anchors a range of cytokines, chemokines and growth factors, all of which are capable of modulating the immune responses. A growing body of evidence shows that ECM proteins themselves are capable of interacting both directly, via a wide range of receptors including integrins and TLRs, and indirectly with immune cells. ECM deposition and remodelling during fibrosis can result in release or formation of ECM-DAMPs, which can drive immune cellular infiltration and sterile inflammation. Both the ECM and immune response are interlinked and integral in driving fibrosis, although their precise interactions in the context of chronic liver disease are poorly understood. This review aims to shed light on the ECM-immune interactions underlying liver disease, in particular fibrosis of different aetiologies, by describing the main ECM intact proteins and ECM-DAMPs with known immune regulatory activity. We also discuss how tissue engineering could provide new opportunities to explore ECM-immune cell interactions in bioreactor-based dynamic 3D models containing intact decellularized ECM scaffolds. A better understanding of these interactions would aid in the identification of new antifibrotic and immunomodulatory targets for treatment and biomarkers in liver disease.
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“In contrast to HMWHAs, low molecular weight hyaluronic acids (LMWHAs) are released during ECM damage or degradation, which act as DAMPs and drive inflammatory responses such as enhancing immune cells chemotaxis, DCs maturation, and M1 polarization of macrophages via the same receptors (CD44 and TLRs) [63, 100].”
From Immunogenicity of decellularized extracellular matrix scaffolds: a bottleneck in tissue engineering and regenerative medicine (2023) · cites this paper as [100]
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“Activation of these receptors accompanies a decrease in DC maturation and promotion in the polarization of macrophages toward M2 phenotype besides differentiation of T cells into regulatory phenotype and induction of apoptosis in activated T cells.”
From Immunogenicity of decellularized extracellular matrix scaffolds: a bottleneck in tissue engineering and regenerative medicine (2023) · cites this paper as [100]
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“Immunomodulatory traits of dECM scaffolds are largely attributed to the ability of their collagens to trigger leukocyte-associated immunoglobulin-like receptors-1 (LAIR-1) of immune cells and consequently downregulation of immune cell activity [100].”
From Immunogenicity of decellularized extracellular matrix scaffolds: a bottleneck in tissue engineering and regenerative medicine (2023) · cites this paper as [100]
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“In another example, high molecular weight hyaluronic acids (HMWHAs), well-known GAGs of dECM, exert anti-inflammatory effects by impeding antigen-antibody interaction and triggering toll-like receptors (TLRs), a subgroup of PRRs, and CD44 receptors of innate and adaptive immune cells.”
From Immunogenicity of decellularized extracellular matrix scaffolds: a bottleneck in tissue engineering and regenerative medicine (2023) · cites this paper as [100]
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“ECM is a reservoir for the cryptic particles that activate or suppress inflammation and orchestrates innate and adaptive immune responses [100, 101].”
From Immunogenicity of decellularized extracellular matrix scaffolds: a bottleneck in tissue engineering and regenerative medicine (2023) · cites this paper as [100]
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“For instance, harsh decellularization procedures may unveil certain cryptic helical and terminal antigenic sites of collagen, prompting the initiation of antibody production against the ECM [73].”
From Liver tissue engineering using decellularized scaffolds: Current progress, challenges, and opportunities (2024) · cites this paper as [73]
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Metadata
- Authors
- McQuitty, C. E., Williams, R., Chokshi, S., & Urbani, L.
- Affiliations
- King's College London (GB)
- Corresponding author
- Urbani, Luca
- Venue
- Frontiers in Immunology
- Publisher
- Frontiers Media SA
- Published
- 2020-11-11
- Volume
- 11
- Pages
- 574276-574276
- ISSN
- 1664-3224 (ISSN-L)
- PMC
- PMC7686550
- OpenAlex
- W3098031338
- Cited by
- 146
- References
- 446
- Citations by year
- 2026: 23 · 2025: 22 · 2024: 34 · 2023: 31 · 2022: 19 · 2021: 17
- FWCI
- 2.23
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Immunology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Keywords
- extracellular matrix, chronic liver disease, liver fibrosis, damage-associated molecular patterns, sterile inflammation, integrins, TLRs, immune cell infiltration, tissue engineering, biomarkers
- MeSH terms
- Anti-Inflammatory Agents, Extracellular Matrix, Humans, Inflammation, Liver, Liver Cirrhosis, Liver Diseases, Cytokines, Extracellular Matrix Proteins, Immunomodulation
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