Review
Fragments of extracellular matrix as mediators of inflammation

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Abstract

Classically, the extracellular matrix (ECM) was viewed as a supporting structure for stabilizing the location of cells in tissues and for preserving the architecture of tissues. This conception has changed dramatically over the past few decades with discoveries that ECM has profound influences on the structure, viability, and functions of cells. Much of the data supporting this new paradigm has been obtained from studies of normal and pathological structural cells such as fibroblasts, smooth muscle cells, and malignant cells, as, for example, breast cancer epithelial cells. However, there has also been recognition that effects of ECM on cells extend to inflammatory cells. In this context, attention has been drawn to fragments of ECM components. In this review, we present information supporting the concept that proteolytic fragments of ECM affect multiple functions and properties of inflammatory and immune cells. Our focus is particularly upon neutrophils, monocytes, and macrophages and fragments derived from collagens, elastin, and laminins. Hyaluronan fragments, although they are not products of proteolysis, are also discussed, as they are a notable example of ECM fragments that exhibit important effects on inflammatory cells. Further, we summarize some exciting recent developments in this field as a result of mouse models in which defined ECM fragments and their receptors are clearly implicated in inflammation in vivo. Thus, this review underscores the idea that proteolysis of ECM may well have implications that go beyond modifying the structural environment of cells and tissues.

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).

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