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The role of matrix metalloproteinases in autoimmune damage to the central and peripheral nervous system
Journal of Neuroimmunology 107 (2000) 140–147 www.elsevier.com / locate / jneuroin
The role of matrix metalloproteinases in autoimmune damage to the central and peripheral nervous system Hans-Peter Hartung*, Bernd C. Kieseier ¨ , Auenbruggerplatz 22, 8036 Graz, Austria Department of Neurology, Karl-Franzens-Universitat
Abstract Members of the family of matrix metalloproteinases (MMPs) have been implicated in the pathogenesis of inflammatory demyelination. MMPs apparently mediate important steps in the genesis of inflammatory demyelination, such as cell migration, blood–brain / nerve barrier breakdown, demyelination, and cytokine activation. This review will highlight in vitro as well as in vivo findings, which support the importance of this group of proteases in the pathogenesis of inflammatory demyelinating disorders of the central and peripheral nervous system. 2000 Elsevier Science B.V. All rights reserved. Keywords: Matrix metalloproteinases; Inflammatory demyelination; Multiple sclerosis; Guillain–Barre´ syndrome
1. Matrix metalloproteinases
1.1. Structure and regulation The matrix metalloproteinases (MMPs) or matrixins comprise a large subfamily of endoproteinases that share structural domains (Fig. 1). Other related subfamily members of an even larger superfamily include astacin, thermolysin, and the serratia and venom metalloproteinases. All these enzymes have a catalytic zinc-binding domain in common that includes a sequence motif HEXXH in which Glu (E) acts as a catalytic base (Krane, 1994; Woessner, 1994; Rawlings and Barrett, 1995). The matrixin subfamily of matrix metalloproteinases consists of at least 23 members and comprises the collagenases, gelatinases, stromelysins, matrilysin, metalloelastase, and membrane-type metalloproteinases, each of which is the product of a different gene (Table 1). Whereas the membrane type MMPs are bound to the cellular surface (Takino et al., 1995), all other MMPs are secreted into the extracellular space by a wide range of cell types as latent pro-enzymes requiring activation by proteolytic cleavage of an amino-terminal domain to expose the active catalytic site (Birkedal-Hansen, 1995). The regulation of MMP activity is strictly controlled at three different levels (Ries
*Corresponding author. Tel.: 143-316-385-2981; fax: 143-316325520. E-mail address: [email protected] (H.-P. Hartung).
Fig. 1. Based on the presence of distinct structural domains MMPs can be divided into several subclasses.
0165-5728 / 00 / $ – see front matter 2000 Elsevier Science B.V. All rights reserved. PII: S0165-5728( 00 )00225-3
H.-P. Hartung, B.C. Kieseier / Journal of Neuroimmunology 107 (2000) 140 – 147 Table 1 The matrix metalloproteinase family Group
MMP
Enzyme
Collagenases
MMP-1 MMP-8 MMP-13 MMP-x a
Interstitial collagenase Neutrophil collagenase Collagenase-3 Collagenase-4
Gelatinases
MMP-2 MMP-9
Gelatinase A Gelatinase B
Stromelysins
MMP-3 MMP-10 MMP-11
Stromelysin-1 Stromelysin-2 Stromelysin-3
Matrilysin
MMP-7
Matrilysin
MT-MMPs
MMP-14 MMP-15 MMP-16 MMP-17
MT-MMP-1 MT-MMP-2 MT-MMP-3 MT-MMP-4
Others
MMP-12 MMP-x MMP-x MMP-19
Macrophage-metalloelastase Enamelysin Xenopus MMP not determined
a
x, not defined.
and Petrides, 1995): gene transcription, pro-enzyme activation, and activity of tissue inhibitors of metalloproteinases (TIMPs). Various cytokines, such as tumor necrosis factora (TNF-a) (Unemori et al., 1991), interleukin-1 (Lyons et al., 1993), transforming growth factor-b (TGF-b) (Edwards et al., 1987), and eicosanoids, such as prostaglandin E 2 (Busiek et al., 1995), can directly induce or suppress MMP expression at the transcriptional level. However, the regulatory effect is more likely to be dependent on the MMP signal transduction / synthesis cascade within a stimulated cell type rather than on the cytokine acting as a ligand, since the same cytokine can have either an inducible or a suppressive effect on MMP expression in
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different cell types. Furthermore, corticosteroids and progesterone are known to suppress transcription. Once synthesized MMPs are secreted as inactive zymogens. The activation of most of these propeptides involves sequential exogenous or endogenous cleavage steps, destabilizing the cysteine–zinc interaction, modifying the enzyme conformation, and allowing further exogenous or autocatalytic processing to the final active form (Murphy et al., 1994). MMPs and other proteinases, such as plasmin, are known to modulate this process. The activated forms are subject to inhibition by TIMPs (Kleiner and Stetler-Stevenson, 1993; Overall, 1994), which are ubiquitously expressed in the extracellular milieu and form a complex, of 1:1 stoichiometry, with the endoproteinases (Stetler-Stevenson et al., 1989). Moreover, proteinase inhibitors such as a 2 -macroglobulin also play a regulatory role (Nagase et al., 1994) (Fig. 2).
1.2. Functional implications MMPs have broad, but not necessarily overlapping substrate specificities. They can degrade all protein components of the extracellular matrix (ECM), such as collagen, elastin, fibronectin, and laminin (Chandler et al., 1997). In many physiological and pathological processes ECM degradation is an important step, in which MMPs and their inhibitors appear to be indispensable (BirkedalHansen, 1995; Shapiro, 1998). Physiological conditions include wound healing, angiogenesis, and bone remodeling. Pathological conditions encompass tumor invasion, metastasis, inflammation and osteoarthritis (Woessner, 1994; Giannelli et al., 1997; Wilson et al., 1997). MMPs appear to be important for ECM degradation, thus a finely tuned regulation is essential: any imbalance in favor of inhibitors can lead to fibrotic processes, whereas any
Fig. 2. The regulation of MMP synthesis and secretion is dependent on various factors. Most MMPs are secreted as inactive zymogens which require extracellular activation. This process is strictly governed by natural inhibitors to ensure a balance between proteolytic activity and fibrosis.
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increase in enzymatic activity will result in tissue destruction or cell invasion (Birkedal-Hansen, 1995). Recent in vitro studies extended the spectrum of MMP substrates to pro-forms of MMPs (Crabbe et al., 1994; Vassalli and Pepper, 1994), enzyme inhibitors, cell-membrane bound adhesion molecules, cytokine precursors, and cytokine receptors. Nevertheless, it still remains difficult to judge the contributory effect of known MMPs to the release of surface cytokines and receptors, which impacts markedly on the orchestration of immunoinflammatory responses. Further avenues of research should lead to a better understanding of MMP involvement in this process.
2. MMPs and inflammatory demyelination
2.1. In vitro-based evidence Recent in vitro studies suggest that at least two processes in the pathogenesis of inflammatory demyelination are mediated by MMPs: (1) gelatinase B seems to promote trans-basement membrane migration of T lymphocytes (Leppert et al., 1995). This observation implies an important role for MMPs in the process of T cell migration from the blood into the CNS or PNS. (2) MMPs appear to be involved in the process of demyelination. Myelin basic protein (MBP), a major protein component of the myelin sheath in the central nervous system (CNS) and potentially an important autoantigen, as well as P0, a protein component of peripheral myelin, are substrates of proteolytic MMP activity (Table 2) (Chandler et al., 1995). Furthermore, evidence is increasing that MMPs may participate in regulating the expression of the cell death signaling molecule FasL (Mariani et al., 1995).
2.2. Lessons from relevant animal models Experimental autoimmune encephalomyelitis (EAE) and experimental autoimmune neuritis (EAN) are animal models for inflammatory demyelinating diseases of the CNS and peripheral nervous system (PNS), respectively. Based on observations in these two model diseases, Table 2 Various MMPs degrade protein components of the myelin sheath (Chandler et al., 1995) Name
MMP-No.
MBP a digestion
P0 degradation
Interstitial collagenase Neutrophil collagenase Gelatinase A Gelatinase B Stromelysin-1 Matrilysin Macrophage metalloelastase MT-MMP-1
MMP-1 MMP-8 MMP-2 MMP-9 MMP-3 MMP-7 MMP-12 MMP-14
1 2 1 1 1 1 2 1
1 2 1 1 1 1 2 1
a
MBP, myelin basic protein.
evidence is strengthening that MMPs at multiple checkpoints are key to the pathogenesis of inflammatory demyelination (Pagenstecher et al., 1998). In the CNS, the intracerebral injection or induction of MMP-2, MMP-7, MMP-8, and MMP-9 results in breakdown of the extracellular matrix, leukocyte recruitment, and opening of the BBB in rats (Rosenberg et al., 1992, 1994; Anthony et al., 1998). In EAE, increased levels of gelatinase B are detectable in the cerebrospinal fluid (CSF) of diseased animals (Gijbels et al., 1993) and immunohistochemistry localized this MMP to infiltrating mononuclear cells and to the perivascular space (Fig. 3) (Kieseier et al., 1998b). Studies investigating the clinical course of EAE found increased mRNA expression patterns of MMP-7 and MMP-9 coincident with peak disease severity, emphasizing a key role of these two MMPs in the pathogenesis of CNS inflammation (Clements et al., 1997; Kieseier et al., 1998b). Inhibition of MMP activity suppressed the development and abrogated clinical EAE in a dose-dependent way (Gijbels et al., 1994; Hewson et al., 1995; Matyszak and Perry, 1996). In chronic relapsing EAE a synthetic MMP inhibitor was shown to completely block acute and to reverse established severe disease; in this study mRNAs for TNF-a and the cell death signaling molecule FasL were found to be downregulated, whereas mRNA for the anti-inflammatory cytokine IL-4 was upregulated (Liedtke et al., 1998). In analogy, MMP blockade in EAN attenuated disease severity when synthetic inhibitors were administered from symptom onset (Redford et al., 1997). In EAN, selective mRNA upregulation of MMP-3, MMP-7, MMP-9, and MMP-12 has been described during the initial phase of the disease, with peak levels coincident with maximum clinical disease severity (Hughes et al., 1998; Kieseier et al., 1998a). The expression of MMP-7 remained upregulated throughout the recovery phase, pointing to a potential role of this metalloprotease in restoring the integrity of the PNS (Table 3).
2.3. MMPs in inflammatory demyelination of the CNS An emerging body of evidence suggests an involvement of MMPs in the pathogenesis of inflammatory demyelination of the CNS (Yong et al., 1998; Kieseier et al., 1999). MS, the prototypic inflammatory demyelinating disorder of the CNS (Hartung et al., 1995), is thought to result from an aberrant immune response predominantly driven by autoreactive T lymphocytes (Hafler and Weiner, 1989; Raine, 1994; Utz and McFarland, 1994). Pathological hallmarks of MS are perivenular inflammation and demyelination (Raine, 1997). Using immunohistochemistry, MMP-9 can be detected in acute demyelinating MS lesions, and localized to macrophages and astrocytes. The latter continue to express this MMP in chronic lesions. Moreover, white matter
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Fig. 3. Immunohistochemistry for gelatinase B in the spinal cord of a Lewis rat with experimental autoimmune encephalomyelitis at the peak of clinical severity. Arrowheads point to immunoreactivity along the meninges, whereas arrows highlight positive signals for MMP-9, which can be localized around blood vessels and to invading mononuclear cells. (a,b) Immunoreactivity of infiltrating cells, primarily found around blood vessels. Original magnifications: 360; a,b 3600.
perivascular mononuclear cells are found to be positive for gelatinase B (Cuzner et al., 1996; Maeda and Sobel, 1996). Other MMPs identifiable in MS plaques include MMP-1, MMP-2, and MMP-3, all of which are expressed by macrophages, whereas the latter two also localize to astrocytes (Maeda and Sobel, 1996). Increased proteolytic activity was determined in the CSF of MS patients (Cuzner et al., 1978; Gijbels et al., 1992). As demonstrated by gadolinium-enhanced magnetic resonance imaging, raised CSF levels of gelatinase B are associated with a leaky BBB, suggestive of an involvement
of MMP activity in BBB breakdown. In addition, treatment with high-dose methylprednisolone, a drug known to downregulate MMP transcription, reduced both gadolinium-enhancement and CSF levels for MMP-9 (Rosenberg et al., 1996). In MS patients elevated MMP-9 mRNA levels in peripheral venous blood mononuclear cells (PBMNCs) (Lichtinghagen et al., 1999; Ozenci et al., 1999) as well as raised MMP-9 serum levels were detectable and might be useful as a surrogate marker in monitoring disease activity (Leppert et al., 1998; Lee et al., 1999) (Table 4).
Table 3 MMP expression in animal models of inflammatory demyelination a Model
Material
Subject
MMP upregulated
Source
EAE
CNS
mRNA
MMP-7, MMP-9
Protein
MMP-9
Protein mRNA
MMP-9 MMP-7, MMP-9, MMP-3, MMP-14 MMP-7, MMP-9
Clements et al. (1997) Kieseier et al. (1998a,b) Clements et al. (1997) Kieseier et al. (1998a,b) Gijbels et al. (1993) Hughes et al. (1998) Kieseier et al. (1998a,b) Hughes et al. (1998) Kieseier et al. (1998a,b)
EAN
CSF PNS
Protein
a EAE, experimental autoimmune encephalomyelitis; EAN, experimental autoimmune neuritis; CNS, central nervous system; CSF, cerebrospinal fluid; PNS, peripheral nervous system.
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Table 4 MMP expression in inflammatory demyelinating diseases of the central and peripheral nervous system a Disorder
Material
Subject
MMP upregulated
Source
MS
CSF CNS
Protein Protein
PBMNCs
mRNA
MMP-9 MMP-1, MMP-2, MMP-3, MMP-9 MMP-9
Serum
Protein
MMP-9
GBS
PNS
CIDP
CSF PNS
mRNA Protein Protein Protein
MMP-7, MMP-9 MMP-7, MMP-9 MMP-9 MMP-2, MMP-9
Gijbels et al. (1992) Cuzner et al. (1996) Maeda and Sobel (1996) Lichtinghagen et al. (1999) Ozenci et al. (1999) Leppert et al. (1998) Lee et al. (1999) Kieseier et al. (1999) Kieseier et al. (1999) Gijbels et al. (1993) Leppert et al. (1999)
a MS, multiple sclerosis; GBS, Guillain-Barre´ syndrome; CIDP, chronic inflammatory demyelinating polyradiculoneuropathy; CSF, cerebrospinal fluid; CNS, central nervous system; PBMNCs, peripheral blood mononuclear cells; PNS, peripheral nervous system.
However, since the detection of MMPs in the CSF, serum or in the MS lesion does only provide sparse information about the role of proteolytic activity in the pathogenesis of inflammatory demyelination in the CNS, further studies are needed to determine how precisely MMPs operate in this group of disorders. Furthermore, the
role of natural inhibitors must be clarified to elucidate the functionality of these proteases. Recent studies yielded conflicting results regarding the expression pattern of TIMPs in MS patients: Ozenci et al. (1999) described an upregulation of TIMP-1 mRNA in PBMNCs from MS patients, whereas other groups could not detect any change
Fig. 4. Matrix metalloproteinases (MMPs) are thought to play at least four important roles in the genesis of inflammatory demyelination (all marked with arrows): cell migration, opening of the blood–brain / nerve barrier (BBB / BNB), release of the proinflammatory cytokine tumor necrosis factor (TNF) a, and myelin degradation. Mf, macrophage; NO, nitric oxide.
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in TIMP expression (Leppert et al., 1998; Lee et al., 1999; Lichtinghagen et al., 1999). Whether this discrepancy is related to technical differences or is based on different subgroups of patients investigated needs to be clarified in the near future. Evidence is surfacing that especially the correlation of TIMP-1 and MMP-9 might be of greater value in monitoring disease activity in MS.
Acknowledgements
2.4. MMPs in inflammatory demyelination of the PNS
Amberger, V.R., Avellane-Adalid, V., Mensel, T., Baron van Evercooren, A., Schwab, M.E., 1997. European J. Neurosci. 9, 151–162. Anthony, D.C., Miller, K.M., Fearn, S., Townsend, M.J., Opdenakker, G., Wells, G.M.A., Clements, J.M., Chandler, S., Gearing, A.J.H., Perry, V.H., 1998. Matrix metalloproteinase expression in an experimentally induced DTH model of multiple sclerosis in the rat CNS. J. Neuroimmunol. 87, 62–72. Arnason, B.G.W., Soliven, B., 1993. In: Dyck, P.J., Thomas, P.K., Griffin, J.W., Low, P.A., Poduslo, J. (Eds.), Peripheral Neuropathy, Vol. 3, Saunders, Philadelphia, PA, pp. 1437–1497. Birkedal-Hansen, H., 1995. Proteolytic remodeling of extracellular matrix. Curr. Opin. Cell Biol. 7, 728–735. Busiek, D.F., Baragi, V., Nehring, L.C., Parks, W.C., Welgus, H.G., 1995. Matrilysin expression by human mononuclear phagocytes and its regulation by cytokines and hormones. J. Immunol. 154, 6484–6491. Chandler, S., Coates, R., Gearing, A., Lury, J., Wells, G., Bone, E., 1995. Matrix metalloproteinases degrade myelin basic protein. Neurosci. Lett. 201, 223–226. Chandler, S., Miller, K.M., Clements, J.M., Lury, J., Corkill, D., Anthony, D.C.C., Adams, S.E., Gearing, A.J.H., 1997. Matrix metalloproteinases, tumor necrosis factor and multiple sclerosis: an overview. J. Neuroimmunol. 72, 155–161. Clements, J.M., Cossins, J.A., Wells, G.M.A., Corkill, D.J., Helfrich, K., Wood, L.M., Pigott, R., Stabler, G., Ward, G.A., Gearing, A.J.H., Miller, K.M., 1997. Matrix metalloproteinase expression during experimental autoimmune encephalomyelitis and effects of a combined matrix metalloproteinase and tumor necrosis factor-a inhibitor. J. Neuroimmunol. 74, 85–94. Crabbe, T., Smith, B., O’Connell, J., Docherty, A., 1994. Human progelatinase A can be activated by matrilysin. FEBS Lett. 345, 14–16. Cuzner, M.L., Davison, A.N., Rudge, P., 1978. Proteolytic enzyme activity of blood leukocytes and cerebrospinal fluid in multiple sclerosis. Ann. Neurol. 4, 337–344. Cuzner, M.L., Gveric, D., Strand, C., Loughlin, A.J., Paemen, L., Opdenakker, G., Newcombe, J., 1996. The expression of tissue-type plasminogen activator, matrix metalloproteases and endogenous inhibitors in the central nervous system in multiple sclerosis: comparison of stages in lesion evolution. J. Neuropathol. Exp. Neurol. 55, 1194–1204. Edwards, D.R., Murphy, G., Reynolds, J.J., Whitham, S.E., Docherty, A.J., Angel, P., Heath, J.K., 1987. Transforming growth factor beta modulates the expression of collagenase and metalloproteinase inhibitor. EMBO J. 6, 1899–1904. Giannelli, G., Falk-Marzillier, J., Schiraldi, O., Stetler-Stevenson, W.G., Quaranta, V., 1997. Induction of cell migration by matrix metalloprotease-2 cleavage of laminin-5. Science 277, 225–228. Gijbels, K., Masure, S., Carton, H., Opdenakker, G., 1992. Gelatinase in the cerebrospinal fluid of patients with multiple sclerosis and other inflammatory neurological disorders. J. Neuroimmunol. 41, 29–34. Gijbels, K., Proost, P., Carton, H., Billiau, A., Opdenakker, G., 1993. Gelatinase B is present in the cerebrospinal fluid during experimental autoimmune encephalomyelitis and cleaves myelin basic protein. J. Neurosci. Res. 36, 432–440. Gijbels, K., Galardy, R.E., Steinman, L., 1994. Reversal of experimental autoimmune encephalomyelitis with a hydroxamate inhibitor of matrix metalloproteinases. J. Clin. Invest. 94, 2177–2182.
The pathomechanisms implicated in the genesis of inflammatory demyelinating disorders of the PNS are thought to involve both humoral and cellular pathways (Hartung et al., 1996). Demyelination and mononuclear cellular infiltration are the histopathological hallmarks of these diseases (Arnason and Soliven, 1993). Infiltrating cells exhibit their inflammatory capacities through a variety of mediators, such as cytokines, chemokines, eicosanoids, and oxygen radicals (Hartung et al., 1993, 1995). In sural nerve biopsies from patients with Guillain– ´ Barre-syndrome (GBS) increased mRNA expression for MMP-9 and MMP-7 could be demonstrated. This upregulation on the messenger level was associated with increased gelatinolytic activity (Kieseier et al., 1998a). CSF samples from patients diagnosed as GBS displayed increased MMP-9 activity (Gijbels et al., 1992). Recently augmented reactivity of MMP-2 and MMP-9 was also found in sural nerve biopsies from patients with chronic inflammatory demyelinating polyradiculoneuropathy, CIDP (Leppert et al., 1999). However, as evidenced from studies in EAN, MMPs in the inflamed PNS appear not only to promote inflammation but may also exert beneficial effects during regeneration of the damaged nervous system (Table 3).
3. Concluding remarks During recent years evidence has accumulated that MMPs may be important mediators of tissue damage in inflammatory demyelinating diseases of both the CNS and PNS. Actions of this group of proteases appear to be crucial at multiple steps in the genesis of autoimmune demyelination. They are involved in BBB and BNB damage, leukocyte recruitment, myelin destruction, and release of the proinflammatory cytokine TNFa (Fig. 4). In animal models selective MMP inhibitors could be used to prevent or ameliorate inflammatory demyelinating diseases. The downside, though, of this approach could be interference with repair process (Amberger et al., 1997; Uhm et al., 1998). It is hoped that future research can define the role of these proteases in human disease and that compounds specifically targeting MMP activity may enlarge our still restricted therapeutic armamentarium.
Work from the authors’ laboratories was supported by ¨ the Gemeinnutzige Hertie Stiftung.
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The role of matrix metalloproteinases in autoimmune damage to the central and peripheral nervous system Hans-Peter Hartung*, Bernd C. Kieseier ¨ , Auenbruggerplatz 22, 8036 Graz, Austria Department of Neurology, Karl-Franzens-Universitat
Abstract Members of the family of matrix metalloproteinases (MMPs) have been implicated in the pathogenesis of inflammatory demyelination. MMPs apparently mediate important steps in the genesis of inflammatory demyelination, such as cell migration, blood–brain / nerve barrier breakdown, demyelination, and cytokine activation. This review will highlight in vitro as well as in vivo findings, which support the importance of this group of proteases in the pathogenesis of inflammatory demyelinating disorders of the central and peripheral nervous system. 2000 Elsevier Science B.V. All rights reserved. Keywords: Matrix metalloproteinases; Inflammatory demyelination; Multiple sclerosis; Guillain–Barre´ syndrome
1. Matrix metalloproteinases
1.1. Structure and regulation The matrix metalloproteinases (MMPs) or matrixins comprise a large subfamily of endoproteinases that share structural domains (Fig. 1). Other related subfamily members of an even larger superfamily include astacin, thermolysin, and the serratia and venom metalloproteinases. All these enzymes have a catalytic zinc-binding domain in common that includes a sequence motif HEXXH in which Glu (E) acts as a catalytic base (Krane, 1994; Woessner, 1994; Rawlings and Barrett, 1995). The matrixin subfamily of matrix metalloproteinases consists of at least 23 members and comprises the collagenases, gelatinases, stromelysins, matrilysin, metalloelastase, and membrane-type metalloproteinases, each of which is the product of a different gene (Table 1). Whereas the membrane type MMPs are bound to the cellular surface (Takino et al., 1995), all other MMPs are secreted into the extracellular space by a wide range of cell types as latent pro-enzymes requiring activation by proteolytic cleavage of an amino-terminal domain to expose the active catalytic site (Birkedal-Hansen, 1995). The regulation of MMP activity is strictly controlled at three different levels (Ries
*Corresponding author. Tel.: 143-316-385-2981; fax: 143-316325520. E-mail address: [email protected] (H.-P. Hartung).
Fig. 1. Based on the presence of distinct structural domains MMPs can be divided into several subclasses.
0165-5728 / 00 / $ – see front matter 2000 Elsevier Science B.V. All rights reserved. PII: S0165-5728( 00 )00225-3
H.-P. Hartung, B.C. Kieseier / Journal of Neuroimmunology 107 (2000) 140 – 147 Table 1 The matrix metalloproteinase family Group
MMP
Enzyme
Collagenases
MMP-1 MMP-8 MMP-13 MMP-x a
Interstitial collagenase Neutrophil collagenase Collagenase-3 Collagenase-4
Gelatinases
MMP-2 MMP-9
Gelatinase A Gelatinase B
Stromelysins
MMP-3 MMP-10 MMP-11
Stromelysin-1 Stromelysin-2 Stromelysin-3
Matrilysin
MMP-7
Matrilysin
MT-MMPs
MMP-14 MMP-15 MMP-16 MMP-17
MT-MMP-1 MT-MMP-2 MT-MMP-3 MT-MMP-4
Others
MMP-12 MMP-x MMP-x MMP-19
Macrophage-metalloelastase Enamelysin Xenopus MMP not determined
a
x, not defined.
and Petrides, 1995): gene transcription, pro-enzyme activation, and activity of tissue inhibitors of metalloproteinases (TIMPs). Various cytokines, such as tumor necrosis factora (TNF-a) (Unemori et al., 1991), interleukin-1 (Lyons et al., 1993), transforming growth factor-b (TGF-b) (Edwards et al., 1987), and eicosanoids, such as prostaglandin E 2 (Busiek et al., 1995), can directly induce or suppress MMP expression at the transcriptional level. However, the regulatory effect is more likely to be dependent on the MMP signal transduction / synthesis cascade within a stimulated cell type rather than on the cytokine acting as a ligand, since the same cytokine can have either an inducible or a suppressive effect on MMP expression in
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different cell types. Furthermore, corticosteroids and progesterone are known to suppress transcription. Once synthesized MMPs are secreted as inactive zymogens. The activation of most of these propeptides involves sequential exogenous or endogenous cleavage steps, destabilizing the cysteine–zinc interaction, modifying the enzyme conformation, and allowing further exogenous or autocatalytic processing to the final active form (Murphy et al., 1994). MMPs and other proteinases, such as plasmin, are known to modulate this process. The activated forms are subject to inhibition by TIMPs (Kleiner and Stetler-Stevenson, 1993; Overall, 1994), which are ubiquitously expressed in the extracellular milieu and form a complex, of 1:1 stoichiometry, with the endoproteinases (Stetler-Stevenson et al., 1989). Moreover, proteinase inhibitors such as a 2 -macroglobulin also play a regulatory role (Nagase et al., 1994) (Fig. 2).
1.2. Functional implications MMPs have broad, but not necessarily overlapping substrate specificities. They can degrade all protein components of the extracellular matrix (ECM), such as collagen, elastin, fibronectin, and laminin (Chandler et al., 1997). In many physiological and pathological processes ECM degradation is an important step, in which MMPs and their inhibitors appear to be indispensable (BirkedalHansen, 1995; Shapiro, 1998). Physiological conditions include wound healing, angiogenesis, and bone remodeling. Pathological conditions encompass tumor invasion, metastasis, inflammation and osteoarthritis (Woessner, 1994; Giannelli et al., 1997; Wilson et al., 1997). MMPs appear to be important for ECM degradation, thus a finely tuned regulation is essential: any imbalance in favor of inhibitors can lead to fibrotic processes, whereas any
Fig. 2. The regulation of MMP synthesis and secretion is dependent on various factors. Most MMPs are secreted as inactive zymogens which require extracellular activation. This process is strictly governed by natural inhibitors to ensure a balance between proteolytic activity and fibrosis.
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increase in enzymatic activity will result in tissue destruction or cell invasion (Birkedal-Hansen, 1995). Recent in vitro studies extended the spectrum of MMP substrates to pro-forms of MMPs (Crabbe et al., 1994; Vassalli and Pepper, 1994), enzyme inhibitors, cell-membrane bound adhesion molecules, cytokine precursors, and cytokine receptors. Nevertheless, it still remains difficult to judge the contributory effect of known MMPs to the release of surface cytokines and receptors, which impacts markedly on the orchestration of immunoinflammatory responses. Further avenues of research should lead to a better understanding of MMP involvement in this process.
2. MMPs and inflammatory demyelination
2.1. In vitro-based evidence Recent in vitro studies suggest that at least two processes in the pathogenesis of inflammatory demyelination are mediated by MMPs: (1) gelatinase B seems to promote trans-basement membrane migration of T lymphocytes (Leppert et al., 1995). This observation implies an important role for MMPs in the process of T cell migration from the blood into the CNS or PNS. (2) MMPs appear to be involved in the process of demyelination. Myelin basic protein (MBP), a major protein component of the myelin sheath in the central nervous system (CNS) and potentially an important autoantigen, as well as P0, a protein component of peripheral myelin, are substrates of proteolytic MMP activity (Table 2) (Chandler et al., 1995). Furthermore, evidence is increasing that MMPs may participate in regulating the expression of the cell death signaling molecule FasL (Mariani et al., 1995).
2.2. Lessons from relevant animal models Experimental autoimmune encephalomyelitis (EAE) and experimental autoimmune neuritis (EAN) are animal models for inflammatory demyelinating diseases of the CNS and peripheral nervous system (PNS), respectively. Based on observations in these two model diseases, Table 2 Various MMPs degrade protein components of the myelin sheath (Chandler et al., 1995) Name
MMP-No.
MBP a digestion
P0 degradation
Interstitial collagenase Neutrophil collagenase Gelatinase A Gelatinase B Stromelysin-1 Matrilysin Macrophage metalloelastase MT-MMP-1
MMP-1 MMP-8 MMP-2 MMP-9 MMP-3 MMP-7 MMP-12 MMP-14
1 2 1 1 1 1 2 1
1 2 1 1 1 1 2 1
a
MBP, myelin basic protein.
evidence is strengthening that MMPs at multiple checkpoints are key to the pathogenesis of inflammatory demyelination (Pagenstecher et al., 1998). In the CNS, the intracerebral injection or induction of MMP-2, MMP-7, MMP-8, and MMP-9 results in breakdown of the extracellular matrix, leukocyte recruitment, and opening of the BBB in rats (Rosenberg et al., 1992, 1994; Anthony et al., 1998). In EAE, increased levels of gelatinase B are detectable in the cerebrospinal fluid (CSF) of diseased animals (Gijbels et al., 1993) and immunohistochemistry localized this MMP to infiltrating mononuclear cells and to the perivascular space (Fig. 3) (Kieseier et al., 1998b). Studies investigating the clinical course of EAE found increased mRNA expression patterns of MMP-7 and MMP-9 coincident with peak disease severity, emphasizing a key role of these two MMPs in the pathogenesis of CNS inflammation (Clements et al., 1997; Kieseier et al., 1998b). Inhibition of MMP activity suppressed the development and abrogated clinical EAE in a dose-dependent way (Gijbels et al., 1994; Hewson et al., 1995; Matyszak and Perry, 1996). In chronic relapsing EAE a synthetic MMP inhibitor was shown to completely block acute and to reverse established severe disease; in this study mRNAs for TNF-a and the cell death signaling molecule FasL were found to be downregulated, whereas mRNA for the anti-inflammatory cytokine IL-4 was upregulated (Liedtke et al., 1998). In analogy, MMP blockade in EAN attenuated disease severity when synthetic inhibitors were administered from symptom onset (Redford et al., 1997). In EAN, selective mRNA upregulation of MMP-3, MMP-7, MMP-9, and MMP-12 has been described during the initial phase of the disease, with peak levels coincident with maximum clinical disease severity (Hughes et al., 1998; Kieseier et al., 1998a). The expression of MMP-7 remained upregulated throughout the recovery phase, pointing to a potential role of this metalloprotease in restoring the integrity of the PNS (Table 3).
2.3. MMPs in inflammatory demyelination of the CNS An emerging body of evidence suggests an involvement of MMPs in the pathogenesis of inflammatory demyelination of the CNS (Yong et al., 1998; Kieseier et al., 1999). MS, the prototypic inflammatory demyelinating disorder of the CNS (Hartung et al., 1995), is thought to result from an aberrant immune response predominantly driven by autoreactive T lymphocytes (Hafler and Weiner, 1989; Raine, 1994; Utz and McFarland, 1994). Pathological hallmarks of MS are perivenular inflammation and demyelination (Raine, 1997). Using immunohistochemistry, MMP-9 can be detected in acute demyelinating MS lesions, and localized to macrophages and astrocytes. The latter continue to express this MMP in chronic lesions. Moreover, white matter
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Fig. 3. Immunohistochemistry for gelatinase B in the spinal cord of a Lewis rat with experimental autoimmune encephalomyelitis at the peak of clinical severity. Arrowheads point to immunoreactivity along the meninges, whereas arrows highlight positive signals for MMP-9, which can be localized around blood vessels and to invading mononuclear cells. (a,b) Immunoreactivity of infiltrating cells, primarily found around blood vessels. Original magnifications: 360; a,b 3600.
perivascular mononuclear cells are found to be positive for gelatinase B (Cuzner et al., 1996; Maeda and Sobel, 1996). Other MMPs identifiable in MS plaques include MMP-1, MMP-2, and MMP-3, all of which are expressed by macrophages, whereas the latter two also localize to astrocytes (Maeda and Sobel, 1996). Increased proteolytic activity was determined in the CSF of MS patients (Cuzner et al., 1978; Gijbels et al., 1992). As demonstrated by gadolinium-enhanced magnetic resonance imaging, raised CSF levels of gelatinase B are associated with a leaky BBB, suggestive of an involvement
of MMP activity in BBB breakdown. In addition, treatment with high-dose methylprednisolone, a drug known to downregulate MMP transcription, reduced both gadolinium-enhancement and CSF levels for MMP-9 (Rosenberg et al., 1996). In MS patients elevated MMP-9 mRNA levels in peripheral venous blood mononuclear cells (PBMNCs) (Lichtinghagen et al., 1999; Ozenci et al., 1999) as well as raised MMP-9 serum levels were detectable and might be useful as a surrogate marker in monitoring disease activity (Leppert et al., 1998; Lee et al., 1999) (Table 4).
Table 3 MMP expression in animal models of inflammatory demyelination a Model
Material
Subject
MMP upregulated
Source
EAE
CNS
mRNA
MMP-7, MMP-9
Protein
MMP-9
Protein mRNA
MMP-9 MMP-7, MMP-9, MMP-3, MMP-14 MMP-7, MMP-9
Clements et al. (1997) Kieseier et al. (1998a,b) Clements et al. (1997) Kieseier et al. (1998a,b) Gijbels et al. (1993) Hughes et al. (1998) Kieseier et al. (1998a,b) Hughes et al. (1998) Kieseier et al. (1998a,b)
EAN
CSF PNS
Protein
a EAE, experimental autoimmune encephalomyelitis; EAN, experimental autoimmune neuritis; CNS, central nervous system; CSF, cerebrospinal fluid; PNS, peripheral nervous system.
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Table 4 MMP expression in inflammatory demyelinating diseases of the central and peripheral nervous system a Disorder
Material
Subject
MMP upregulated
Source
MS
CSF CNS
Protein Protein
PBMNCs
mRNA
MMP-9 MMP-1, MMP-2, MMP-3, MMP-9 MMP-9
Serum
Protein
MMP-9
GBS
PNS
CIDP
CSF PNS
mRNA Protein Protein Protein
MMP-7, MMP-9 MMP-7, MMP-9 MMP-9 MMP-2, MMP-9
Gijbels et al. (1992) Cuzner et al. (1996) Maeda and Sobel (1996) Lichtinghagen et al. (1999) Ozenci et al. (1999) Leppert et al. (1998) Lee et al. (1999) Kieseier et al. (1999) Kieseier et al. (1999) Gijbels et al. (1993) Leppert et al. (1999)
a MS, multiple sclerosis; GBS, Guillain-Barre´ syndrome; CIDP, chronic inflammatory demyelinating polyradiculoneuropathy; CSF, cerebrospinal fluid; CNS, central nervous system; PBMNCs, peripheral blood mononuclear cells; PNS, peripheral nervous system.
However, since the detection of MMPs in the CSF, serum or in the MS lesion does only provide sparse information about the role of proteolytic activity in the pathogenesis of inflammatory demyelination in the CNS, further studies are needed to determine how precisely MMPs operate in this group of disorders. Furthermore, the
role of natural inhibitors must be clarified to elucidate the functionality of these proteases. Recent studies yielded conflicting results regarding the expression pattern of TIMPs in MS patients: Ozenci et al. (1999) described an upregulation of TIMP-1 mRNA in PBMNCs from MS patients, whereas other groups could not detect any change
Fig. 4. Matrix metalloproteinases (MMPs) are thought to play at least four important roles in the genesis of inflammatory demyelination (all marked with arrows): cell migration, opening of the blood–brain / nerve barrier (BBB / BNB), release of the proinflammatory cytokine tumor necrosis factor (TNF) a, and myelin degradation. Mf, macrophage; NO, nitric oxide.
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in TIMP expression (Leppert et al., 1998; Lee et al., 1999; Lichtinghagen et al., 1999). Whether this discrepancy is related to technical differences or is based on different subgroups of patients investigated needs to be clarified in the near future. Evidence is surfacing that especially the correlation of TIMP-1 and MMP-9 might be of greater value in monitoring disease activity in MS.
Acknowledgements
2.4. MMPs in inflammatory demyelination of the PNS
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The pathomechanisms implicated in the genesis of inflammatory demyelinating disorders of the PNS are thought to involve both humoral and cellular pathways (Hartung et al., 1996). Demyelination and mononuclear cellular infiltration are the histopathological hallmarks of these diseases (Arnason and Soliven, 1993). Infiltrating cells exhibit their inflammatory capacities through a variety of mediators, such as cytokines, chemokines, eicosanoids, and oxygen radicals (Hartung et al., 1993, 1995). In sural nerve biopsies from patients with Guillain– ´ Barre-syndrome (GBS) increased mRNA expression for MMP-9 and MMP-7 could be demonstrated. This upregulation on the messenger level was associated with increased gelatinolytic activity (Kieseier et al., 1998a). CSF samples from patients diagnosed as GBS displayed increased MMP-9 activity (Gijbels et al., 1992). Recently augmented reactivity of MMP-2 and MMP-9 was also found in sural nerve biopsies from patients with chronic inflammatory demyelinating polyradiculoneuropathy, CIDP (Leppert et al., 1999). However, as evidenced from studies in EAN, MMPs in the inflamed PNS appear not only to promote inflammation but may also exert beneficial effects during regeneration of the damaged nervous system (Table 3).
3. Concluding remarks During recent years evidence has accumulated that MMPs may be important mediators of tissue damage in inflammatory demyelinating diseases of both the CNS and PNS. Actions of this group of proteases appear to be crucial at multiple steps in the genesis of autoimmune demyelination. They are involved in BBB and BNB damage, leukocyte recruitment, myelin destruction, and release of the proinflammatory cytokine TNFa (Fig. 4). In animal models selective MMP inhibitors could be used to prevent or ameliorate inflammatory demyelinating diseases. The downside, though, of this approach could be interference with repair process (Amberger et al., 1997; Uhm et al., 1998). It is hoped that future research can define the role of these proteases in human disease and that compounds specifically targeting MMP activity may enlarge our still restricted therapeutic armamentarium.
Work from the authors’ laboratories was supported by ¨ the Gemeinnutzige Hertie Stiftung.
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