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Cited by 146Liver physiology and pathologyLiver Diseases and ImmunityTissue Engineering and Regenerative Medicine

The DOI matches its Crossref record; 445 of the 446 references it cites were found in a registry or an index, and 1 are not checked yet.

Immunomodulatory Role of the Extracellular Matrix Within the Liver Disease Microenvironment

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McQuitty, Claire E., Williams, Roger, Chokshi, Shilpa, Urbani, Luca·2020·Frontiers in Immunology
DOI 10.3389/fimmu.2020.574276PMC PMC7686550
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Abstract

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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Crossref · 10.3389/fimmu.2020.574276

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Figure 1 Interaction between TLR4 expressed on immune cells and extracellular matrix (ECM) proteins/ECM-damage-associated molecular patterns (DAMPs). Schematic that summaries known interactions between TLR4 and individual ECM-DAMPs or ECM proteins and consequent immune responses.
Figure 1 Interaction between TLR4 expressed on immune cells and extracellular matrix (ECM) proteins/ECM-damage-associated molecular patterns (DAMPs). Schematic that summaries known interactions between TLR4 and individual ECM-DAMPs or ECM proteins and consequent immune responses.CC BY · PubMed Central
Figure 2 Immunomodulatory extracellular matrix (ECM) proteins. Schematic that shows ECM proteins with direct and indirect modulation of immune responses. (A) Intact proteins/ECM-damage-associated molecular patterns (DAMPs). Bioactive domains on numerous ECM proteins act as direct ligands for a wide number of immune cell receptors, including toll-like receptors (TLRs) and integrins, and drive a range of inflammatory and immune-suppressive responses. (B) Indirect. Numerous ECM proteins can bind growth factors, harbouring them in the ECM. Growth factors can be released upon ECM remodeling, creating a local inflammatory milieu which drives recruitment and polarization of infiltrating and resident immune cells. (C) ECM-fragments/DAMPs. Active remodeling of the ECM during fibrosis, results in the generation of ECM protein fragments which can be recognized by immune cells as DAMPs. Proteins with more than one mechanism of immunomodulation are indicated in red. Schematic was created using BioRender (https://app.biorender.com).
Figure 2 Immunomodulatory extracellular matrix (ECM) proteins. Schematic that shows ECM proteins with direct and indirect modulation of immune responses. (A) Intact proteins/ECM-damage-associated molecular patterns (DAMPs). Bioactive domains on numerous ECM proteins act as direct ligands for a wide number of immune cell receptors, including toll-like receptors (TLRs) and integrins, and drive a range of inflammatory and immune-suppressive responses. (B) Indirect. Numerous ECM proteins can bind growth factors, harbouring them in the ECM. Growth factors can be released upon ECM remodeling, creating a local inflammatory milieu which drives recruitment and polarization of infiltrating and resident immune cells. (C) ECM-fragments/DAMPs. Active remodeling of the ECM during fibrosis, results in the generation of ECM protein fragments which can be recognized by immune cells as DAMPs. Proteins with more than one mechanism of immunomodulation are indicated in red. Schematic was created using BioRender (https://app.biorender.com).CC BY · PubMed Central
Figure 3 3D-dynamic perfusion-based immune competent systems to study extracellular matrix (ECM). Development of 3D-dynamic immune competent models to study ECM properties in vitro. (A) whole liver decellularization generates an acellular scaffold with maintained vasculature and ECM network. The resulting liver scaffold can be placed in a bioreactor which allows continuous circular perfusion of immune cells through the decellularized liver vasculature, facilitating immune cell:ECM interaction and monitoring of cellular phenotypes. (B) segments of liver tissue can be obtained from patient liver tissue and decellularized to generate acellular liver segments. These can be cultured in a multi-well bioreactor which supports perfusion of immune cells. The multi-well set up allows for direct comparison between eg healthy vs diseased tissue perfused with the same immune cells. Schematic was created using BioRender (https://app.biorender.com).
Figure 3 3D-dynamic perfusion-based immune competent systems to study extracellular matrix (ECM). Development of 3D-dynamic immune competent models to study ECM properties in vitro. (A) whole liver decellularization generates an acellular scaffold with maintained vasculature and ECM network. The resulting liver scaffold can be placed in a bioreactor which allows continuous circular perfusion of immune cells through the decellularized liver vasculature, facilitating immune cell:ECM interaction and monitoring of cellular phenotypes. (B) segments of liver tissue can be obtained from patient liver tissue and decellularized to generate acellular liver segments. These can be cultured in a multi-well bioreactor which supports perfusion of immune cells. The multi-well set up allows for direct comparison between eg healthy vs diseased tissue perfused with the same immune cells. Schematic was created using BioRender (https://app.biorender.com).CC BY · PubMed Central

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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
ORCID
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2020-11-11
Volume
11
Pages
574276-574276
ISSN
1664-3224 (ISSN-L)
DOI
10.3389/fimmu.2020.574276
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
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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