Immunobiology 209 (2004) 51–56

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The role of matrix metalloproteinase 7 in innate immunity

Bernard Burke*

Department of Infection, Immunity and Inflammation, Medical Sciences Building, University of Leicester, Leicester LE1 9HN, UK

Received 5 April 2004; accepted 7 April 2004

Abstract

Matrix metalloproteinase 7 (MMP-7), or matrilysin, is a secreted protease expressed by glandular and mucosalepithelial cells, keratinocytes, fibroblasts and macrophages. As with other MMPs it can act on the extracellular matrixand thereby regulate cell migration and tissue repair. In addition, MMP-7 has an important role in the maintenance ofinnate immunity in organs such as the lungs and intestines where it proteolytically activates anti-bacterial peptides suchas pro-defensins. MMP-7 is also important for mediating proteolytic release of TNF from macrophages. Consistentwith its role in innate immunity, MMP-7 is induced by microbial products and also, unexpectedly, by hypoxia.r 2004 Elsevier GmbH. All rights reserved.

Keywords: Metalloproteinase, hypoxia, macrophages

Matrix metalloproteinases

Matrix metalloproteinases (MMPs) are a large groupof extracellular proteinases which belong to the metal-loproteinase superfamily. MMPs share two conservedregions, the pro-domain, and the catalytic domain,which contains a zinc ion. To date, 28 MMPs have beencharacterised (Lohi et al., 2001). They share a similargene structure, and are believed to have arisen byduplication of an ancestral gene. In general, MMPs areexpressed by activated cells, and have important roles inprocesses such as breakdown of the extracellular matrix,proteolytic processing of secreted proteins and cellmigration (Parks and Shapiro, 2001).

MMP-7

Matrix metalloproteinase (MMP-7) (also referred toas matrilysin) is expressed by exocrine and mucosal

6-223-1401; fax: +44-116-252-3050.

s: bb14@le.ac.uk (B. Burke).

front matter r 2004 Elsevier GmbH. All rights reserved.

io.2004.04.005

epithelial cells in the skin, salivary glands, pancreas,liver, breast, intestine, urogenital tract, the lungs andother tissues. Apart from epithelial cells and keratino-cytes, MMP-7 secretion has been reported only infibroblasts, macrophages, and in neoplastic cells ofepithelial origin, where it is often highly expressed andhas important pro-tumour effects (Wilson and Matri-sian, 1996). MMP-7 is the smallest MMP, at 28 kDa inits proMMP-7 inactive form (19 kDa in its active form),and is one of only two which lack a hemopexin domainat the C-terminus. This regulatory domain is believed tohave a role in determination of substrate specificity andits absence may explain the broad range of proteinscleaved by MMP-7.

Its many substrates include extracellular matrixcomponents such as fibronectin, gelatins, collagen typeIV, laminin and elastin, cleavage of which leads to thebreakdown of the matrix, which is important in cellmigration and tissue remodelling.

MMP-7 also cleaves pro-forms of the proteasesMMP-2 and MMP-9 (Wilson and Matrisian, 1996),leading to their activation. Another proteinase acti-vated by MMP-7 is ADAM28 (a disintegrin and

ARTICLE IN PRESSB. Burke / Immunobiology 209 (2004) 51–5652

metalloproteinase), which is highly expressed by lym-phocytes (Mochizuki et al., 2004).

Role of MMP-7 in innate immunity

One of the main functions of MMP-7 in immunity,following its secretion from glandular and mucosalepithelial cells in the lung and the gut, is proteolyticactivation of a-defensins (cryptdins). a-Defensins are agroup of six cationic anti-bacterial peptides, which actby disrupting bacterial membranes (Ganz, 1999; Yanget al., 2001). They are produced mainly by neutrophilsand monocyte/macrophages (human neutrophil pep-tides (HNP) 1–4) and also by Paneth cells (humandefensins 5 and 6) at the base of the crypts in the smallintestine. They are secreted in response to bacterialproducts such as LPS and lipoteichoic acid (Ayabe et al.,2000). In addition to their direct anti-bacterial, -fungal,and -enveloped virus functions, a-defensins serve todraw together innate and adaptive immunity (Chertovet al., 2000) by acting as chemoattractants for mono-cytes, T-cells and dendritic cells. They are also mitogenicfor epithelial cells and fibroblasts (Murphy et al., 1993),and thus are likely to have a role in wound healing.MMP-7 knockout mice do not activate pro-a-defensinsin the gut to the mature active forms, with the result thatthese mice are highly susceptible to intestinal bacterialinfections (Wilson et al., 1999). MMP-7 also has a rolein releasing the cytokine TNF from macrophages andpossibly other cells. Macrophage-produced MMP-7 hasbeen shown to be necessary for macrophage infiltrationinto disc tissue in a model of herniated disc resorption,in a mechanism involving release of soluble TNF fromthe macrophages (Haro et al., 2000). MMP-7 has beenshown to be capable of cleaving recombinant TNF(Gearing et al., 1994), by a mechanism which isindependent of the main TNF sheddase, TNF-aconverting enzyme (TACE) (Haro et al., 2000). MMP-7 also cleaves other members of the TNF family,including Fas ligand. This ability is responsible for thecorrelation between expression of MMP-7 by tumoursand resistance to the chemotherapeutic agent doxorubi-cin, which acts via Fas ligand (Mitsiades et al., 2001). Itmay well be that other roles of FasL in the regulation ofadaptive immunity (Dockrell, 2003) are also influencedby MMP-7. It has been suggested that certain popula-tions of cells, for example thioglycollate-elicited perito-neal macrophages, rely on MMP-7 to process TNF andrelated cytokines (reviewed in Haro et al., 2000).

MMP-7 also has an important role in the control oftransepithelial neutrophil migration, by cleaving synde-can-1, the main heparan sulphate proteoglycan onepithelia, from the extracellular matrix. This establishesa chemotactic gradient of the chemokine KC, which is

released by damaged epithelia, and which specificallybinds to syndecan-1. In MMP-7 knockout mice,neutrophils cannot cross the lung epithelium, andaccumulate in the interstitium between the capillariesand the epithelium (Li et al., 2002).

Factors regulating MMP-7

MMP-7 was thought to be constitutively expressed byglandular and mucosal epithelial cells at high levels, butit has been shown that it is in fact strongly induced bybacteria. Expression is not detectable in the smallintestines of germ-free mice, but was induced whenthese animals were colonised by a Gram negativecommensal bacterium (Lopez-Boado et al., 2000).However, recent work on a-defensin activation in thePaneth cells of germ-free mice implies that MMP-7 isproduced constitutively, albeit at very low levels (Ayabeet al., 2002). The Gram negative bacterium Helicobacter

pylori up-regulates MMP-7 in vivo and in vitro (Craw-ford et al., 2003), and it has been suggested that the highlevels of MMP-7 produced may pre-dispose to gastriccancer (Bebb et al., 2003) In addition, expression ofMMP-7 is induced up to 75 fold in a human colon-derived cell line by adherent Gram-negative bacteria, viaa mechanism which is not dependent on LPS (Lopez-Boado et al., 2000). Lack of induction of MMP-7 incolon cells by LPS is to be expected because theepithelial cells lining the gut do not express Toll-likereceptor 4 (TLR4), the specific receptor for LPS. This ispresumably an adaptation to the high concentrations ofLPS generated in the gut by commensal bacteria(Kobayashi and Flavell, 2004). It has been suggestedthat MMP-7 induction in gut epithelial cells may sharemechanisms with the human B-defensin BD-2, whichalso has a role in innate immunity at epithelial surfacesand is induced by bacteria and a variety of pro-inflammatory cytokines but not by LPS (Lopez-Boadoet al., 2001). Similarly, airway epithelial cells, whichreside in sites lacking commensal bacteria, but which areexposed to high levels of foreign antigens, also expressvery little TLR4 under normal conditions (Monick et al.,2003). LPS (derived from the bacterium Pseudomonas

aeruginosa) is only capable of low level induction ofMMP-7 in the lung epithelium-derived cell line Calu-3(Lopez-Boado et al., 2001). Further investigation of theeffect of LPS from a wider range of bacteria on MMP-7expression by primary airway epithelial cells is requiredto clarify the degree to which LPS induces MMP-7 inthe lung.

LPS is a strong inducer of MMP-7 in primary humanbone marrow-derived promonocytes and peripheralblood monocytes (Busiek et al., 1992). The finding ofinduction by LPS in monocytes is in contrast to a later

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finding in which the U937 monocytic cell line was foundnot to show this effect (Lopez-Boado et al., 2000). Thisdisparity may be due to the fact that U937 is aneoplastic cell line representing a monoblast and there-fore is unlikely to show typical monocyte responses.

MMP-7 is expressed at very high levels in the lungs ofcystic fibrosis sufferers, who often carry heavy bacterialloads of pathogens including P. aeruginosa. Lopez-Boado et al. (2001) identified flagellin, the precursor ofbacterial flagella (derived from P. aeruginosa in theseexperiments), as a potent inducer of MMP-7 expressionin lung epithelia. Flagellin is recognised by TLR5, andinterestingly this TLR has been shown to be expressedby the basolateral surface, but not the apical surface, ofepithelia. Thus bacteria secreting flagellin must enter theepithelium, a characteristic of pathogenic rather thancommensal organisms, in order to trigger an inflamma-tory response (and hence MMP-7), which provides amechanism for the immune system to distinguishbetween them (Gewirtz et al., 2001).

In addition to molecules derived from micro-organ-isms, a wide range of cytokines and other substanceshave been shown to up-regulate MMP-7 to varyingextents (Table 1). Others have been shown to affectMMP-7 expression in cancer cell lines, but these havebeen excluded for the purposes of this review. MMP-7,as well as being expressed continuously at epithelialsites in response to normal commensal flora, is likely tobe further up regulated by cytokines in many sitesof inflammation. This would cause increased activa-tion of defensin-type anti-pathogen peptides as well asincreased release of soluble TNF from macrophages.MMP-7 therefore has roles both in activatingproteins of the innate immune system to directly destroy

Table 1. Factors regulating MMP-7 in primary cells

Factor Effect Cell type

Signalling molecules

Glucocorticoids Induction Macrophage

IFN-g Inhibition Macrophage

IL-1a Induction Chondrocyte

IL-4 Inhibition Macrophage

IL-10 Inhibition Macrophage

Retinoids Induction Macrophage

TNF Induction Chondrocyte

Other

Nitroglycerine Induction Macrophage

Gram -ve bacteria Induction Mucosal epi

Flagellin Induction Lung epithe

LPS Induction Macrophage

Opsonised zymosan Induction Macrophage

HIV infection Induction Peripheral b

Hypoxia Induction Macrophage

aThe references are not comprehensive, but give examples of seminal pap

micro-organisms, and also in helping to activate otherelements of both the innate and acquired immunesystem by triggering cytokine cascades. Not surpris-ingly, MMP-7 has been identified as an early markerof bacterially induced inflammation (Lopez-Boadoet al., 2001).

MMPs are required to remodel the regenerated tissuewhich is formed after the resolution of an infection orinjury, by facilitating regression of new blood vesselsand modification of the extracellular matrix to maximisemechanical strength (reviewed by Crowther et al., 2001).MMP-7 has an important role in this tissue remodellingas evidenced by the impaired wound healing observed inknockout mice, the most severe impairment observed inany MMP knockout to date (Parks and Shapiro, 2001;Wilson et al., 1999). Part of this healing defect may alsorelate to the role of MMP-7 in clearing the inevitableinfections which occur in wounds, via its role as afacilitator of the innate immune response. Its role as anactivator of other MMPs such as MMP-2 and -9(Wilson and Matrisian, 1996) is also likely to be ofsignificance in wound healing. Expression of MMP-7 inwounds may be due, at least in part, to cytokines whichoccur in damaged tissue such as TNF, IL-1 and -6(Crowther et al., 2001), and also to hypoxia (lowoxygen). Hypoxia, characteristic of inflamed sites suchas wounds, and also of tumours, has recently beenshown to up-regulate MMP-7. cDNA array analysis ofprimary human monocyte-derived macrophages after 5days in culture indicated a 4-fold increase in MMP-7mRNA in response to hypoxia (0.5% oxygen for 16 h),which was confirmed using RT-PCR analysis and byreporter constructs driven by the human MMP-7promoter (Burke et al., 2003).

Referencea

s Busiek et al. (1995)

s Busiek et al. (1995)

s Ohta et al. (1998)

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thelial cells Lopez-Boado et al. (2000)

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The time course of MMP-7 expression in inflamedsites from the point of damage or infection to the pointof completion of healing has not been determined, so itsrelative importance in the early (infection clearance) andlate (tissue remodelling) stages of wound healing isunknown.

Expression of MMP-7 by monocyte/

macrophages

MMP-7 is expressed in monocyte/macrophages atmany different stages of differentiation, ranging frombone marrow-derived promonocytes and peripheralblood monocytes (Busiek et al., 1992), and newlyextravasated macrophages (Busiek et al., 1995), tolipid-laden macrophages in atherosclerotic lesions (Hal-pert et al., 1996). A recent study has indicated thatMMP-7 expression by primary human monocyte-derived macrophages increases with differentiationstatus, reaching a plateau after 5 days culture in vitro(Filippov et al., 2003). This contrasts with the earlystudy by Busiek et al. (1992), who showed that MMP-7expression did not increase after 7 days of maturation inculture, and that mature alveolar macrophages did notappear to express MMP-7. Similarly, a study by Gibbset al. (1999) has suggested that rat alveolar macrophagesdo not express MMP-7. In situ hybridisation indicatesthat expression of MMP-7 within a population ofmonocytes is extremely variable (Busiek et al., 1995).The same study also demonstrated that MMP-7 expres-sion by monocyte/macrophages is affected by a widerange of stimuli including cytokines, prostaglandins,gluococorticoids and retinoids. These findings illustratethat the precise isolation and culture conditions used,for example contamination of media with bacterial-derived substances, or the degree of cell–cell contact,which has been shown to regulate MMP-7 in certain celltypes (Borchers et al., 1997) may markedly affect theresults obtained in different experiments with monocyte/macrophages.

A possible role of macrophage-expressed MMP-7 isfacilitation of migration through the extracellular matrix,since MMP-7 is known to promote migration of epithelialcells (Parks and Shapiro, 2001) and metastasis of cancercells (Powell et al., 1993). This is likely to be due to theability of MMP-7 to break down the extracellular matrix,and also to its abilities to cleave cell surface proteins suchas E-cadherin, which normally serve to strengthen cell–cellinteractions. The ectodomain of E-cadherin released byMMP-7 action also appears to have a pro-migration effect(Noe et al., 2001). In addition, up-regulation of MMP-7 bymacrophages, for example in response to LPS or otherbacterial products, would also stimulate innate immuneresponses at sites of inflammation by release of TNF from

macrophages or other cells, and activation of anti-pathogenic and chemotactic proteins such as the defensins.

Transcriptional regulation of the MMP-7 gene

The MMP-7 promoter contains a number of tran-scription factor binding sites which are conservedamong MMPs, including CIZ (Nakamoto et al., 2000),b-catenin/TCF, AP-1 and Ets/PEA3 sites (Crawfordet al., 2001; Gaire et al., 1994; Nakamoto et al., 2000).The zinc finger protein CIZ, which interacts with thedocking protein Cas, has been shown to up-regulateMMP-7 and MMPs –1 and –3 (Nakamoto et al., 2000).Interestingly, overexpression of Cas, which transmitssignals from integrins, has been shown to promote cellmotility. CIZ shuttles between the nucleus and focaladhesions, and it has been speculated that it is atranscription factor involved in cell movement (Naka-moto et al., 2000). It is likely to be advantageous formigrating cells to up-regulate MMP expression tofacilitate the process, and the CIZ/Cas system may bea way of coordinating migration and MMP expression.In another link between cell adherence and MMP-7expression, the proto-oncoprotein b-catenin, whichlocalises to adherens junctions where it interacts withthe cell-cell adhesion molecule E-cadherin (Aberle et al.,1996), has been shown to act synergistically with thePEA3 family to up-regulate the MMP-7 promoterduring tumourigenesis (Crawford et al., 2001). b-catenintransactivates genes via its interaction with members ofthe TCF/LEF-1 DNA binding protein family. b-cateninalone is not sufficient, under some conditions, to up-regulate the MMP-7 promoter in the absence of Etsfamily members, and interestingly TCF and Ets sites arefound in close proximity in the MMP-7 promoter. Thispairing of TCF and Ets sites is found in a number ofpromoters from species as diverse as Man and Droso-phila, and represents an evolutionarily strongly con-served promoter module (Crawford et al., 2001). TheEts transcription factor PEA3 sub-family plays animportant role in regulation of MMP-7 transcription,binding to the Ets sites in the promoter, and cannot besubstituted for by other Ets family members. Inactiva-tion of the Ets sites markedly affects activation by c-Jun(acting via the AP-1 site) and b-catenin (acting viathe TCF sites), and expression of any of the PEA3subfamily enables responsiveness to c-Jun andb-catenin. AP-1 seems to play a supporting role inmodulating the activity of the MMP-7 promoter,requiring interaction with other factors, particularlyPEA3 sub-family members, since inactivation of the AP-1 site affects only activation by c-Jun (Crawford et al.,2001). Additional transcription factors believed to playa role in MMP-7 regulation include STAT3, which

ARTICLE IN PRESSB. Burke / Immunobiology 209 (2004) 51–56 55

appears to mediate induction by fibroblast growthfactor-1 (Udayakumar et al., 2002). Interestingly,although MMP-7 is induced by microbial structureslike LPS, which act mainly via the NF-kB pathway, thepromoter of MMP-7 does not contain an obvious NF-kB motif. Another unknown is the mechanism leadingto enhanced activity of the MMP-7 promoter duringhypoxia.

Prospects

While most of the activities of MMP-7 are clearlybeneficial, in certain circumstances such as in cancer orin the lungs of cystic fibrosis sufferers, excessive levels ofthis protease are undesirable. Inhibitors of MMP-7 andother MMPs are being developed, and hold promise forfuture therapies. A number of inhibitors, such as BB-1101 (Leib et al., 2001), inhibit both MMP-7 and TACE,and therefore may be of great potential utility in limitingTNF release in such conditions as sepsis. In conclusion,MMP-7 has an important role in the activation ofseveral immune mechanisms, and it is likely that the listof its activities is far from complete.

Acknowledgements

The author gratefully acknowledges the financialsupport of The Leicestershire Medical Research Foun-dation, and the Royal Society.

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