Fragments of extracellular matrix as mediators of inflammation

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.

Fig. 1. The elastin receptor complex

A 67-kDa enzymatically inactive, alternatively spliced variant of human β-galactosidase is identical to the previously described elastin binding protein (EBP). This protein binds the X-Gly-X-X-Pro-Gly (XGXXPG) motif in ECM proteins, such as elastin, laminins, collagen type IV, and fibrillin-1. EBP complexes with the 55-kDa protective protein-cathepsin A (PPCA) and the 61-kDa neuraminidase (Neu-1) on the cell surface. This receptor complex, after interaction with XGXXPG motifs, via Neu-1, transduces intracellular signals that trigger numerous cellular responses (provided by Aleksander Hinek, see (Hinek, 1988; Hinek, 1996; Privitera, 1998)).

Fig. 2. The “linker” regions of the mouse laminin α chains

The amino acid sequences of the “linker” region between the coiled-coil and the globular domains of two of the five the mouse laminin α chains are compared. Dashes are incorporated to maintain alignment. The SIKVAV-like sequences (underlined) in these laminin chains activate inflammatory cells (Corcoran, 1995; Khan, 1997; Khan, 2000; Adair-Kirk, 2003). Modified from (Adair-Kirk, 2003) with permission; Copyright 2003 The American Association of Immunologists, Inc.

Fig. 3. Chemotactic activity of a collagen-derived fragment

Early in an inflammatory response, human neutrophils react to CXC chemokines, such as IL-8, by following the chemotactic gradient and emigrating into the interstitial space. This chemotactic response depends upon the ability of IL-8 to engage either of its two receptors, CXCR1 and CXCR2. Proteolytic cleavage of type I collagen, presumably by MMPs and subsequent acetylation, generates an acetylated pro-gly-pro, which mimics a key motif of IL-8, and thus stimulates CXCR1 and CXCR2, prolonging the influx of neutrophils. Taken from (Henson, 2006) with permission.