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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2007

Open Access 01-12-2007 | Research

Downregulation of membrane type-matrix metalloproteinases in the inflamed or injured central nervous system

Authors: Henrik Toft-Hansen, Alicia A Babcock, Jason M Millward, Trevor Owens

Published in: Journal of Neuroinflammation | Issue 1/2007

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Abstract

Background

Matrix metalloproteinases (MMPs) are thought to mediate cellular infiltration in central nervous system (CNS) inflammation by cleaving extracellular matrix proteins associated with the blood-brain barrier. The family of MMPs includes 23 proteinases, including six membrane type-MMPs (MT-MMPs). Leukocyte infiltration is an integral part of the pathogenesis of autoimmune inflammation in the CNS, as occurs in multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE), as well as in the response to brain trauma and injury. We have previously shown that gene expression of the majority of MMPs was upregulated in the spinal cord of SJL mice with severe EAE induced by adoptive transfer of myelin basic protein-reactive T cells, whereas four of the six MT-MMPs (MMP-15, 16, 17 and 24) were downregulated. The two remaining MT-MMPs (MMP-14 and 25) were upregulated in whole tissue.

Methods

We used in vivo models of CNS inflammation and injury to study expression of MT-MMP and cytokine mRNA by real-time RT-PCR. Expression was also assessed in microglia sorted from CNS by flow cytometry, and in primary microglia cultures following treatment with IFNγ.

Results

We now confirm the expression pattern of MT-MMPs in the B6 mouse, independent of effects of adjuvant. We further show expression of all the MT-MMPs, except MMP-24, in microglia. Microglia isolated from mice with severe EAE showed statistically significant downregulation of MMP-15, 17 and 25 and lack of increase in levels of other MT-MMPs. Downregulation of MT-MMPs was also apparent following CNS injury. The pattern of regulation of MT-MMPs in neuroinflammation showed no association with expression of the proinflammatory cytokines TNFα, IL-1β, or IFNγ.

Conclusion

CNS inflammation and injury leads to downregulation in expression of the majority of MT-MMPs. Microglia in EAE showed a general downregulation of MT-MMPs, and our findings suggest that MT-MMP levels may inversely correlate with microglial reactivity.
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Literature
1.
2.
Yong VW, Power C, Forsyth P, Edwards DR: Metalloproteinases in biology and pathology of the nervous system. Nat Rev Neurosci. 2001, 2 (7): 502-511.CrossRefPubMed
3.
Clements JM, Cossins JA, Wells GM, Corkill DJ, Helfrich K, Wood LM, Pigott R, Stabler G, Ward GA, Gearing AJ, Miller KM: Matrix metalloproteinase expression during experimental autoimmune encephalomyelitis and effects of a combined matrix metalloproteinase and tumour necrosis factor-alpha inhibitor. J Neuroimmunol. 1997, 74 (1-2): 85-94.CrossRefPubMed
4.
Gijbels K, Galardy RE, Steinman L: Reversal of experimental autoimmune encephalomyelitis with a hydroxamate inhibitor of matrix metalloproteases. J Clin Invest. 1994, 94 (6): 2177-2182.PubMedCentralCrossRefPubMed
5.
Hewson AK, Smith T, Leonard JP, Cuzner ML: Suppression of experimental allergic encephalomyelitis in the Lewis rat by the matrix metalloproteinase inhibitor Ro31-9790. Inflamm Res. 1995, 44 (8): 345-349.CrossRefPubMed
6.
Liedtke W, Cannella B, Mazzaccaro RJ, Clements JM, Miller KM, Wucherpfennig KW, Gearing AJ, Raine CS: Effective treatment of models of multiple sclerosis by matrix metalloproteinase inhibitors. Ann Neurol. 1998, 44 (1): 35-46.CrossRefPubMed
7.
Kalebic T, Garbisa S, Glaser B, Liotta LA: Basement membrane collagen: degradation by migrating endothelial cells. Science. 1983, 221 (4607): 281-283.CrossRefPubMed
8.
Sato H, Takino T, Okada Y, Cao J, Shinagawa A, Yamamoto E, Seiki M: A matrix metalloproteinase expressed on the surface of invasive tumour cells. Nature. 1994, 370 (6484): 61-65.CrossRefPubMed
9.
Hernandez-Barrantes S, Bernardo M, Toth M, Fridman R: Regulation of membrane type-matrix metalloproteinases. Semin Cancer Biol. 2002, 12 (2): 131-138.CrossRefPubMed
10.
Nuttall RK, Pennington CJ, Taplin J, Wheal A, Yong VW, Forsyth PA, Edwards DR: Elevated membrane-type matrix metalloproteinases in gliomas revealed by profiling proteases and inhibitors in human cancer cells. Mol Cancer Res. 2003, 1 (5): 333-345.PubMed
11.
Coussens LM, Fingleton B, Matrisian LM: Matrix metalloproteinase inhibitors and cancer: trials and tribulations. Science. 2002, 295 (5564): 2387-2392.CrossRefPubMed
12.
Overall CM, Kleifeld O: Tumour microenvironment - opinion: validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy. Nat Rev Cancer. 2006, 6 (3): 227-239.CrossRefPubMed
13.
Zucker S, Pei D, Cao J, Lopez-Otin C: Membrane type-matrix metalloproteinases (MT-MMP). Curr Top Dev Biol. 2003, 54: 1-74.CrossRefPubMed
14.
Stamenkovic I: Extracellular matrix remodelling: the role of matrix metalloproteinases. J Pathol. 2003, 200 (4): 448-464.CrossRefPubMed
15.
Strongin AY, Collier I, Bannikov G, Marmer BL, Grant GA, Goldberg GI: Mechanism of cell surface activation of 72-kDa type IV collagenase. Isolation of the activated form of the membrane metalloprotease. J Biol Chem. 1995, 270 (10): 5331-5338.CrossRefPubMed
16.
Zucker S, Drews M, Conner C, Foda HD, DeClerck YA, Langley KE, Bahou WF, Docherty AJ, Cao J: Tissue inhibitor of metalloproteinase-2 (TIMP-2) binds to the catalytic domain of the cell surface receptor, membrane type 1-matrix metalloproteinase 1 (MT1-MMP). J Biol Chem. 1998, 273 (2): 1216-1222.CrossRefPubMed
17.
Toft-Hansen H, Nuttall RK, Edwards DR, Owens T: Key metalloproteinases are expressed by specific cell types in experimental autoimmune encephalomyelitis. J Immunol. 2004, 173 (8): 5209-5218.CrossRefPubMed
18.
Weaver A, Goncalves da Silva A, Nuttall RK, Edwards DR, Shapiro SD, Rivest S, Yong VW: An elevated matrix metalloproteinase (MMP) in an animal model of multiple sclerosis is protective by affecting Th1/Th2 polarization. Faseb J. 2005, 19 (12): 1668-1670.PubMed
19.
Fuentes ME, Durham SK, Swerdel MR, Lewin AC, Barton DS, Megill JR, Bravo R, Lira SA: Controlled recruitment of monocytes and macrophages to specific organs through transgenic expression of monocyte chemoattractant protein-1. J Immunol. 1995, 155 (12): 5769-5776.PubMed
20.
Toft-Hansen H, Buist R, Sun XJ, Schellenberg A, Peeling J, Owens T: Metalloproteinases Control Brain Inflammation Induced by Pertussis Toxin in Mice Overexpressing the Chemokine CCL2 in the Central Nervous System. J Immunol. 2006, 177 (10): 7242-7249.CrossRefPubMed
21.
Babcock AA, Kuziel WA, Rivest S, Owens T: Chemokine expression by glial cells directs leukocytes to sites of axonal injury in the CNS. J Neurosci. 2003, 23 (21): 7922-7930.PubMed
22.
Wells JE, Rice TK, Nuttall RK, Edwards DR, Zekki H, Rivest S, Yong VW: An adverse role for matrix metalloproteinase 12 after spinal cord injury in mice. J Neurosci. 2003, 23 (31): 10107-10115.PubMed
23.
Millward JM, Caruso M, Campbell IL, Gauldie J, Owens T: IFN-gamma-induced chemokines synergize with pertussis toxin to promote T cell entry to the central nervous system. J Immunol. 2007, 178 (12): 8175-8182.CrossRefPubMed
24.
Babcock AA, Wirenfeldt M, Holm T, Nielsen HH, Dissing-Olesen L, Toft-Hansen H, Millward JM, Landmann R, Rivest S, Finsen B, Owens T: Toll-like receptor 2 signaling in response to brain injury: an innate bridge to neuroinflammation. J Neurosci. 2006, 26 (49): 12826-12837.CrossRefPubMed
25.
Bar-Or A, Nuttall RK, Duddy M, Alter A, Kim HJ, Ifergan I, Pennington CJ, Bourgoin P, Edwards DR, Yong VW: Analyses of all matrix metalloproteinase members in leukocytes emphasize monocytes as major inflammatory mediators in multiple sclerosis. Brain. 2003, 126 (Pt 12): 2738-2749.CrossRefPubMed
26.
Nuttall RK, Silva C, Hader W, Bar-Or A, Patel KD, Edwards DR, Yong VW: Metalloproteinases are enriched in microglia compared with leukocytes and they regulate cytokine levels in activated microglia. Glia. 2007, 55 (5): 516-526.CrossRefPubMed
27.
Ghirnikar RS, Lee YL, Eng LF: Inflammation in traumatic brain injury: role of cytokines and chemokines. Neurochem Res. 1998, 23 (3): 329-340.CrossRefPubMed
28.
Stoll G, Jander S, Schroeter M: Detrimental and beneficial effects of injury-induced inflammation and cytokine expression in the nervous system. Adv Exp Med Biol. 2002, 513: 87-113.PubMed
29.
Borden P, Heller RA: Transcriptional control of matrix metalloproteinases and the tissue inhibitors of matrix metalloproteinases. Crit Rev Eukaryot Gene Expr. 1997, 7 (1-2): 159-178.CrossRefPubMed
30.
Schmid CD, Sautkulis LN, Danielson PE, Cooper J, Hasel KW, Hilbush BS, Sutcliffe JG, Carson MJ: Heterogeneous expression of the triggering receptor expressed on myeloid cells-2 on adult murine microglia. J Neurochem. 2002, 83 (6): 1309-1320.PubMedCentralCrossRefPubMed
31.
Takahashi K, Rochford CD, Neumann H: Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2. J Exp Med. 2005, 201 (4): 647-657.PubMedCentralCrossRefPubMed
32.
McCawley LJ, Matrisian LM: Matrix metalloproteinases: they're not just for matrix anymore!. Curr Opin Cell Biol. 2001, 13 (5): 534-540.CrossRefPubMed
33.
Kang T, Yi J, Guo A, Wang X, Overall CM, Jiang W, Elde R, Borregaard N, Pei D: Subcellular distribution and cytokine- and chemokine-regulated secretion of leukolysin/MT6-MMP/MMP-25 in neutrophils. J Biol Chem. 2001, 276 (24): 21960-21968.CrossRefPubMed
34.
Rostworowski M, Balasingam V, Chabot S, Owens T, Yong VW: Astrogliosis in the neonatal and adult murine brain post-trauma: elevation of inflammatory cytokines and the lack of requirement for endogenous interferon-gamma. J Neurosci. 1997, 17 (10): 3664-3674.PubMed
Metadata
Title
Downregulation of membrane type-matrix metalloproteinases in the inflamed or injured central nervous system
Authors
Henrik Toft-Hansen
Alicia A Babcock
Jason M Millward
Trevor Owens
Publication date
01-12-2007
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2007
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/1742-2094-4-24

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