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Matrix metalloproteinases as modulators of inflammation and innate immunity

Nature Reviews Immunology volume 4, pages 617629 (2004) | Download Citation

Subjects

Abstract

As their name implies, matrix metalloproteinases are thought to be responsible for the turnover and degradation of the extracellular matrix. However, matrix degradation is neither the sole nor the main function of these proteinases. Indeed, as we discuss here, recent findings indicate that matrix metalloproteinases act on pro-inflammatory cytokines, chemokines and other proteins to regulate varied aspects of inflammation and immunity.

Key points

  • Inflammation comprises the detection and response to injury and pathogens, the accumulation and intervention of cells that eliminate invading microorganisms and infected host cells, and the repair of tissues that are damaged by the initial insult, trauma or the responses of the host.

  • Numerous effector proteins regulate and coordinate repair, leukocyte recruitment, and immunity, and the activity of many of these effectors is controlled by limited proteolysis. So, proteinases provide an important control that regulates the varied cellular processes defining inflammation.

  • Matrix metalloproteinases (MMPs) constitute a family of 24 mammalian extracellular or membrane-bound proteinases that function in wound repair, mucosal defence, inflammation and acquired immunity. MMPs accomplish these varied tasks by acting on a variety of protein substrates, such as antimicrobial peptides, adhesion proteins, receptors, cytokines, chemokines and extracellular-matrix proteins.

  • In particular, several MMPs regulate the activity of chemokines, either directly or indirectly, thereby controlling many aspects of inflammation and immunity. Many chemokines are directly cleaved by MMPs, thereby resulting in enhancement, inactivation or antagonism of chemokine activities. By contrast, others chemokines are regulated by MMP cleavage of substrates that bind, retain and concentrate the chemotactic molecules in particular locations: that is, they establish chemokine gradients. This results in a coordinated influx of immune effector cells, including neutrophils, monocytes and eosinophils. So, MMPs actively participate in the evolution and outcome of the inflammatory response.

  • MMP7 is used as an example of an MMP that has diverse functions in the innate immune response. In the gut, MMP7 participates in the barrier function of the epithelium by activating antimicrobial peptides. In response to epithelial injury, MMP7 is expressed by cells at the wound edge, and its activity is required for re-epithelialization. This is thought to occur through the shedding of epithelial (E)-cadherin ectodomains, which loosen cell–cell contacts. Furthermore, at the wound site, MMP7 sheds chemokine-bound syndecan-1, a transmembrane proteoglycan, which in turn guides the transepithelial influx of neutrophils.

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Affiliations

  1. University of Washington, Harborview Medical Center, Department of Medicine, Box 359640, 325 9th Avenue, Seattle, Washington 98104, USA.

    • William C. Parks
  2. Department of Medicine, University of Washington School of Medicine, Seattle, Washington 98195, USA.

    • William C. Parks
  3. Department of Pathology, University of Washington School of Medicine, Seattle, Washington 98195, USA.

    • Carole L. Wilson
  4. Department of Internal Medicine (Molecular Medicine), Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA.

    • Yolanda S. López-Boado

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The authors declare no competing financial interests.

Corresponding author

Correspondence to William C. Parks.

Glossary

PRO-DOMAIN

The matrix metalloproteinase (MMP) pro-peptide region (or pro-domain) contains 80 amino acids, typically with a hydrophobic residue at the amino terminus. It also contains the highly conserved sequence PRCXXPD, where X denotes any amino acid. The thiol group of the cysteine residue in this sequence ligates with the zinc ion that is held by the histidine residues in the catalytic domain of the MMP. In this state, the enzyme is stable and inactive and is known as a zymogen.

CATALYTIC-DOMAIN

The typical matrix metalloproteinase catalytic domain contains 160–170 residues, including the binding sites for the structural (calcium and zinc) and catalytic (zinc) metal ions. The 50–54 residues at the carboxyl terminus of the catalytic domain include a highly conserved HEXXHXXGXXH sequence (where X denotes any amino acid), which includes a glutamic acid residue (E) that provides the nucleophile that severs peptide bonds and histidine residues that coordinate the zinc ions.

MET TURN

On the carboxy side of the zinc active site, matrix metalloproteinases have a methionine residue that is always conserved. This residue is part of a 1,4-β-turn that loops the polypeptide chain beneath the catalytic zinc ion and forms a hydrophobic base for the zinc-binding site.

ADAM

A disintegrin and metalloproteinase family of proteases. They contain disintegrin-like and metalloproteinase-like domains and are involved in the regulation of developmental processes, cell–cell interactions and protein processing, including ectodomain shedding.

CLAN

The superfamily of metalloenzymes includes more than 200 members. It has been divided into eight clans based on the similarity of protein folding characteristics and 40 families according to evolutionary relationships. The matrix-metalloproteinase family belongs to clan MB, the members of which have three histidine residues as zinc-binding ligands in the consensus sequence HEXXHXXGXXH (where X denotes any amino acid).

HINGE REGION

A domain that is typically 75 residues and links the catalytic domain to the hemopexin-like domain of most matrix metalloproteinases.

HEMOPEXIN-LIKE DOMAIN

This matrix-metalloproteinase domain comprises 200 residues and contains four repeats that resemble hemopexin and vitronectin. It is not essential for catalytic activity but does modulate substrate specificity and binding to tissue inhibitors of metalloproteinases.

GLYCOSYLPHOSPHAT- IDYLINOSITOL (GPI)-ANCHORING SIGNALS

A glycolipid modification that is usually located at the carboxyl terminus and anchors proteins to the external surface of the plasma membrane.

GELATIN-BINDING DOMAINS

These domains contain three fibronectin-like modules (also known as fibronectin type II modules) and are present in the catalytic domain of both matrix metalloproteinase 2 and -9.

CYSTEINE-SWITCH MECHANISM

The pro-peptide maintains a matrix metalloproteinase (MMP) in an inactive state. When the interaction between the conserved cysteine residue in the pro-domain and the active site zinc ion is disrupted (for example, by proteolytic removal of the pro-peptide or by the action of organomercurials and chaotropic agents on the thiol of the cysteine residue), the active site becomes accessible, and the MMP has been 'activated'. The pro-domain does not need to be removed for a proMMP to acquire activity; only disruption of the zinc–thiol interaction is absolutely required.

TIMPs

Tissue inhibitors of metalloproteinases. A family of four (TIMP1, -2, -3 and -4) endogenous matrix-metalloproteinase (MMP) inhibitors that bind the catalytic site in activated enzymes. TIMP1 and TIMP3 also bind the hemopexin-like domain of the MMP9 and MMP13 zymogens, whereas TIMP2, -3 and -4 can bind this domain in the MMP2 zymogen.

CHEMOKINES

A family of structurally related, small glycoproteins (70–90 amino acids) that have potent leukocyte activation and/or chemotactic activity. They have pivotal roles in innate and acquired immunity. These molecules, of which there are more than 50, are classified into four subfamilies depending on the arrangement of the amino-terminal conserved cysteine residues: CC-, CXC-, C- and CX3C-chemokines (where X denotes any amino acid). In general, CC-chemokines attract monocytes, lymphocytes, basophils and eosinophils, whereas CXC-chemokines are chemotactic for neutrophils.

INNATE IMMUNITY

The term generally refers to innate pathogen-recognition systems, as well as to antimicrobial peptides. Innate immunity comprises immediate responses that are generated without the requirement for memory of, or prior exposure to, the pathogen. It is mostly mediated by receptors that have broad specificity (such as Toll-like receptors): that is, receptors that recognize many related pathogen-associated molecular patterns.

RE-EPITHELIALIZATION

A mechanism of repair that involves epithelial-cell proliferation and migration across a denuded surface to re-establish cell contact and close a wound. During re-epithelialization, cells receive and process cues from a new microenvironment (that is, the exposed wound) and coordinate various responses, including the induction of matrix metalloproteinases and pro-inflammatory mediators, and the activation and expression of integrins.

DEFENSINS

A class of antimicrobial peptides that have activity against Gram-positive and Gram-negative bacteria, fungi and viruses. Defensins are classified into two main categories on the basis of the position of conserved cysteine and hydrophobic residues and the linkages of disulphide bonds: α-defensins are produced by intestinal Paneth cells and neutrophils, and β-defensins are expressed by most epithelial cells. A third category, the θ-defensins, arises from the splicing of two α-defensin-related peptides into a circular molecule; at present, these defensins have been detected only in the neutrophils of rhesus macaques.

NEUTROPHIL TRANSEPITHELIAL MIGRATION

During bacterial infections at mucosal sites, neutrophils migrate from the vasculature through the interstitial compartment and across the epithelial barrier. The activation and migration of neutrophils into lungs also contributes to inflammatory tissue injury and remodelling of tissue architecture

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DOI

https://doi.org/10.1038/nri1418

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