The International Journal of Biochemistry & Cell Biology
ReviewFragments of extracellular matrix as mediators of inflammation
Introduction
Extracellular matrix (ECM) is a complex mixture of proteins, proteoglycans, and glycosaminoglycans that supports cells and tissue architecture. In recent decades it has become apparent that ECM also provides signals affecting cell adhesion, shape, migration, proliferation/survival, and differentiation. Thus, ECM components have domains that interact with specific cell surface receptors. Classic examples of ECM interactions with cells involve the cell surface receptor family of integrins. However, there are also non-integrin-based interactions between ECM and cell surface receptors. The ligand domain in an ECM component may be cryptic, that is, exposed only after the ECM is modified. These bioactive ECM domains, designated “matricryptins” (Davis, Bayless, Davis, & Meininger, 2000; Schenk & Quaranta, 2003), have functions distinct from the parent molecule. Proteolytically released ECM fragments with bioactivity are called “matrikines” (Duca, Floquet, Alix, Haye, & Debelle, 2004; Maquart, Pasco, Ramont, Hornebeck, & Monboisse, 2004).
Matrikines in wound healing and tumor progression have been the topic of several recent reviews (Duca et al., 2004; Hornebeck & Maquart, 2003; Labat-Robert & Robert, 2005; Labat-Robert & Robert, 2007; Maquart, Bellon, Pasco, & Monboisse, 2005; Maquart et al., 2004; Tran, Griffith, & Wells, 2004). This brief commentary reviews recent developments in the expanding topic of ECM fragments as mediators of inflammation. Although degradation of ECM may affect inflammation via release of cytokines associated with the ECM (Alon et al., 1994, Hershkoviz et al., 1994; Hershkoviz, Goldkorn, & Lider, 1995; Vaday et al., 2001), this aspect of ECM and inflammation is beyond the scope of this review. This review will focus on the pro- and anti-inflammatory effects of ECM fragments, with emphasis on fragments generated from laminins, collagens, elastin, and hyaluronan. First, in vitro evidence for inflammatory effects of ECM fragments is summarized; then, results from recent in vivo studies are presented.
Section snippets
In vitro analysis of the effects of ECM fragments on inflammatory cells: general comments
Many in vitro studies involving either proteolytic ECM fragments or synthetic peptides corresponding to ECM sequences indicate that ECM fragments can affect inflammatory cells. The applicability of such studies to inflammatory processes in vivo is uncertain, however, because these types of studies typically have been simple, involving a single ECM fragment in solution and a single cell type. Despite their limitations, studies of this type can be useful in a number of ways: they demonstrate the
In vivo effects of ECM fragments on inflammatory cells: general comments
As described above, there is considerable evidence that fragments or peptides derived from ECM components modulate many activities of inflammatory cells in vitro. To determine whether these findings apply in vivo is difficult. Several pieces of data are needed: (1) induction of inflammatory effects when ECM-derived fragments or synthetic ECM domains are introduced into tissues; (2) detection of similar ECM fragments in biological samples, such as tissue extracts, serum, synovial fluid, or
Summary
ECM components have domains that interact with receptors on inflammatory cells. Thus, exposure or release of these matrix-derived domains from intact ECM molecules, as may occur by proteolytic activity during inflammation and tissue injury, can lead to a variety of inflammatory cell responses. Recent studies clearly show that bioactive domains of ECM can be generated in vivo. Receptors for active domains in several ECM components have been determined at the molecular level and the intracellular
Conclusion
In addition to its classical role of providing structural support for cells and tissues, fragments released from many ECM components trigger various responses in inflammatory and immune cells.
Acknowledgements
This work was funded by the Francis Family Foundation (TLA-K), the Alan A. and Edith L. Wolf Charitable Trust/Barnes-Jewish Hospital Foundation (RMS), and NHLBI/NIH P01 HL 29594 (RMS).
References (76)
- et al.
Laminin SIKVAV peptide induction of monocyte/macrophage prostaglandin E2 and matrix metalloproteinases
J. Biol. Chem.
(1995) - et al.
Regulation of tissue injury responses by the exposure of matricryptic sites within extracellular matrix molecules
Am. J. Pathol.
(2000) - et al.
Elastin fragments induce IL-1beta upregulation via NF-kappaB pathway in melanoma cells
J. Invest. Dermatol.
(2006) - et al.
The elastin receptor complex transduces signals through the catalytic activity of its Neu-1 subunit
J. Biol. Chem.
(2007) - et al.
Elastin as a matrikine
Crit. Rev. Oncol. Hematol.
(2004) - et al.
SIKVAV, a laminin alpha1-derived peptide, interacts with integrins and increases protease activity of a human salivary gland adenoid cystic carcinoma cell line through the ERK 1/2 signaling pathway
Am. J. Pathol.
(2007) - et al.
Monocyte chemotactic activity in human abdominal aortic aneurysms: role of elastin degradation peptides and the 67-kD cell surface elastin receptor
J. Vasc. Surg.
(2002) - et al.
Proteolyzed matrix as a template for the regulation of tumor progression
Biomed. Pharmacother.
(2003) - et al.
Hyaluronan fragments synergize with interferon-gamma to induce the C-X-C chemokines mig and interferon-inducible protein-10 in mouse macrophages
J. Biol. Chem.
(1998) - et al.
Type IV collagen-binding proteins of neutrophils: possible involvement of L-selectin in the neutrophil binding to type IV collagen
Blood
(1996)