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Metalloproteinases and their natural inhibitors in inflammation and immunity

Subjects

Key Points

  • Accumulating evidence has uncovered a crucial role for the matrix metalloproteinase (MMP) and adamalysin families of proteases in immune responses. MMP and disintegrin metalloproteinase (ADAM) expression is tightly regulated in immune and stromal cells during inflammation. Active metalloproteinases modify immune substrates or cleave transmembrane receptors, thereby affecting cell–cell communication and intracellular signalling.

  • Metalloproteinase activity regulates signal transduction pathways that are central to immunity, such as tumour necrosis factor receptor, interleukin-6 receptor, epidermal growth factor receptor and Notch signalling, thereby controlling the kinetics, the amplitude and the combination of molecular signals released within a tissue. Through these pathways, the metalloproteinase–TIMP axis guides cell death versus cell survival cues, and affects the final outcome after inflammation.

  • Metalloproteinases influence innate immune cell migration to the site of infection through the modification of chemokines and they control innate immune cell clearance through apoptosis and phagocytosis. Aspects of adaptive immunity, such as direct lymphocyte communication and natural killer cell function, are also affected by metalloproteinase-mediated proteolysis.

  • Metalloproteinase dysregulation occurs in many inflammatory and autoimmune diseases, and this is highlighted by the many spontaneous and induced inflammatory phenotypes observed in mice that lack one or more metalloproteinases or their inhibitors.

Abstract

Over the past 50 years, steady growth in the field of metalloproteinase biology has shown that the degradation of extracellular matrix components represents only a fraction of the functions performed by these enzymes and has highlighted their fundamental roles in immunity. Metalloproteinases regulate aspects of immune cell development, effector function, migration and ligand–receptor interactions. They carry out ectodomain shedding of cytokines and their cognate receptors. Together with their endogenous inhibitors TIMPs (tissue inhibitor of metalloproteinases), these enzymes regulate signalling downstream of the tumour necrosis factor receptor and the interleukin-6 receptor, as well as that downstream of the epidermal growth factor receptor and Notch, which are all pertinent for inflammatory responses. This Review discusses the metalloproteinase family as a crucial component in immune cell development and function.

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Figure 1: Established and recently uncovered modes of MMP, ADAM and TIMP regulation.
Figure 2: Metalloproteinases balance immunity by regulating epithelial cell–immune cell crosstalk at mucosal surfaces.
Figure 3: Metalloproteinases modify molecules important in immune cell migration and function.
Figure 4: Metalloproteinase dysregulation during atherosclerosis.

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Acknowledgements

The authors thank members of R.K.'s laboratory for a critical read of the manuscript. Our research is supported by funding from Canadian Institutes of Health Research (CIHR), Canadian Breast Cancer Foundation (CBCF), Canadian Cancer Society Research Institute (CCSRI), Heart & Stroke Foundation of Canada, and Ontario Institute of Cancer Research (OICR). A.M. held a CIHR studentship.

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Glossary

Matrix metalloproteinases

(MMPs; also known as matrixins). A family of related enzymes within the metzincin clan. An enzyme is generally assigned to this family if it has three characteristics: sequence homology to MMP1, a cysteine switch within the pro-peptide domain that contributes to the regulation of pro-peptide activation, and a zinc ion-binding motif within the catalytic domain. Members of the MMP family can also be categorized by function — that is, as collagenases, gelatinases, stromelysins, matrilysins, membrane-type MMPs and others.

Disintegrin metalloproteinases

(ADAMs; also known as adamalysins). A family of related enzymes within the metzincin clan, first characterized as the degradative enzymes in snake venom. Besides their catalytic zinc ion-dependent domain, ADAMs share disintegrin-like and cysteine-rich domains.

Metzincin clan

Enzymes within the metzincin clan are named for their zinc ion-binding methionine-turn sequences. The metzincin clan includes astacins, serralysins, adamalysins, matrix metalloproteinases, snapalysins and leishmanolysins. In this Review, we use the term 'metalloproteinase' to refer primarily to the adamalysins and matrix metalloproteinases.

CpG islands

Sequences of 0.5–2 kilobases that are rich in CpG dinucleotides. They are mostly located upstream of housekeeping genes and also of some tissue-specific genes. They are constitutively non-methylated in all animal cell types.

M1 macrophages

Macrophages that are activated by Toll-like receptor ligands (such as lipopolysaccharide) and interferon-γ. M1 macrophages express pro-inflammatory cytokines and inducible nitric oxide synthase, among others.

M2 macrophages

Macrophages that are induced by interleukin-4 (IL-4) or IL-13. M2 macrophages express arginase 1, the mannose receptor CD206 and the IL-4 receptor α-chain, among others.

MI2 NURD complex

The MI2 (also known as CHD4) nucleosome remodelling and deacetylase (NURD) complex, which is expressed across a broad range of tissues, controls gene regulation through its dual capacity to both deacetylate histones (through the histone deacetylase 1 (HDAC1) and/or HDAC2 subunits), and to remodel chromatin using the ATPase activity of its MI2 proteins.

Immunological synapse

A large junctional structure that is formed at the cell surface between a T cell and an antigen-presenting cell (APC); it consists of molecules required for adhesion and signalling. This structure is important in establishing antigen-specific T cell activation, T cell adhesion and polarity, is influenced by the cytoskeleton and transduces highly controlled secretory signals, thereby enabling the directed release of cytokines or lytic granules towards the APC or the target cell.

Atherosclerotic plaques

Atherosclerotic lesions consisting of a fibrotic cap surrounding a lipid-rich core. The lesions are the site of inflammation, lipid accumulation and cell death. They are also known as atheromas.

Foam cells

Macrophages that localize to sites of early stage inflammation in the vessel wall subsequently ingest oxidized low-density lipoprotein and slowly become overloaded with lipids. They are called foam cells because of their appearance, including numerous cytoplasmic vesicles containing cholesterol and other lipids. Foam cells eventually die and attract more macrophages, which further propagates the inflammation in the vessel wall.

Type 2 diabetes

A disorder of glucose homeostasis that is characterized by inappropriately increased blood glucose levels and resistance of tissues to the action of insulin. Recent studies indicate that inflammation in adipose tissue, liver and muscle contributes to the insulin-resistant state that is characteristic of type 2 diabetes mellitus.

Stellate cells

Also known as Ito cells, these are types of pericytes found in the hepatic perisinusoidal space that are the main reservoirs of retinol in the liver.

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Khokha, R., Murthy, A. & Weiss, A. Metalloproteinases and their natural inhibitors in inflammation and immunity. Nat Rev Immunol 13, 649–665 (2013). https://doi.org/10.1038/nri3499

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