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The impact of the extracellular matrix on inflammation

Abstract

The advent of in situ immunology and intravital analyses of leukocyte movement in tissues has drawn attention to the previously neglected extracellular matrix (ECM) and its role in modulating immune cell behaviour in inflamed tissues. The ECM exists in different biochemical and structural forms; both their individual components and three-dimensional ultrastructure impart specific signals to cells that modulate basic functions that are important for the early steps in inflammation, such as immune cell migration into inflamed tissues and immune cell differentiation. In chronically inflamed tissues, aberrant ECM expression and fragments of the ECM that are derived from tissue-remodelling processes can influence immune cell activation and survival, thereby actively contributing to immune responses at these sites.

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Figure 1: Leukocyte infiltration into inflamed tissues.
Figure 2: Cellular and ECM layers that are encountered by leukocytes infiltrating CNS post-capillary venules.
Figure 3: Potential modes of ECM-mediated activation of immune cells.

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Acknowledgements

I apologize to those individuals whose work I have not been able to cite owing to space limitations. I thank R. Hallmann, P. Bruckner, D. Vestweber, P. Yurchenco and V. Gerke for critical reading of the manuscript and for helpful suggestions. Special thanks go to C. Wu for help with figure 2. Some of the research that is described in this Review was supported by the German Research Foundation (DFG), the Swedish Research Council (VR), the Medical Faculty of the University of Münster, Germany, and the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreements 201,024 and 202,213 (European Stroke Network).

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Glossary

Intravital microscopy

A technique that is used for the examination of biological processes, such as leukocyte–endothelial cell interactions, in living tissues. In general, translucent tissues are used, such as the mesentery or cremaster muscle. These tissues can be exposed and mounted for microscopic observation.

Extracellular matrix

(ECM). The secreted products of many cell types that form an organized scaffold for cell support.

Extravasation

The cellular process in which circulating leukocytes bind to and migrate through the endothelium into the underlying tissue.

Cell adhesion molecules

Proteins (for example, CD99, CD99 antigen-like-2 (CD99L2) and platelet/endothelial cell adhesion molecule 1 (PECAM1)) that are located between adjacent endothelial cells but that are also expressed by neutrophils, monocytes and lymphocytes and are known to have important roles in leukocyte transmigration of the endothelium in inflammation. CD99 (also known as MIC2) is a small highly glycosylated glycoprotein with no known similarity to any other protein family. CD99L2 is distantly related to CD99 and has 32% sequence identity; PECAM1 is a member of the immunoglobulin supergene family.

Pericytes

Cells that are embedded in the vascular basement membrane of microvessels and that are thought to be derived from the vascular smooth muscle cell lineage. They make close cellular contact with endothelial cells and this interaction is essential for the maintenance of vessel function, as well as for the regulation of angiogenesis and vascular remodelling.

Tensile strength

The maximum load that a material can support during stretching without irreversible disruption and is expressed per unit area. When stresses less than the tensile strength are removed, a material returns either completely or partially to its original shape and size.

Diapedesis

The migration of leukocytes across the endothelium. This migration generally occurs by squeezing through the junctions between adjacent endothelial cells, although in some settings leukocytes have been shown to pass through transiently formed gaps in the cytoplasm of endothelial cells. It is the last step in the leukocyte–endothelial cell adhesion cascade, which includes tethering, triggering, tight adhesion and transmigration.

Perivascular cuff

The immune cell infiltrate that is immediately adjacent to the outer surface of the post-capillary venule wall and, in the case of central nervous system vessels, is bordered by the inner endothelial cell basement membrane and the outer parenchymal basement membrane.

Delayed-type hypersensitivity

(DTH). A cellular immune response to antigen that develops over a period of 24–72 hours. The response is characterized by the infiltration of T cells and monocytes and depends on the production of TH1-type cytokines.

Filopodia

Slender cytoplasmic projections that extend from the leading edge of migrating cells.

Osteopontin

An extracellular matrix protein that supports the adhesion and migration of inflammatory cells. It has recently been recognized as an immunoregulatory TH1-type cytokine.

Toll-like receptor family

(TLR family). A family of receptors that are unique to microorganisms that recognize conserved products (such as lipopolysaccharide) known as pathogen-associated molecular patterns (PAMPs), as well as damage-associated molecular patterns (DAMPs). TLRs signal to the host that a microbial pathogen is present or that tissue damage has occurred.

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Sorokin, L. The impact of the extracellular matrix on inflammation. Nat Rev Immunol 10, 712–723 (2010). https://doi.org/10.1038/nri2852

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