Inflammatory Proprotein Convertase-Matrix Metalloproteinase Proteolytic Pathway in Antigen-presenting Cells as a Step to Autoimmune Multiple Sclerosis

Abstract

Multiple sclerosis (MS) is a disease of the central nervous system with autoimmune etiology. Susceptibility to MS is linked to viral and bacterial infections. Matrix metalloproteinases (MMPs) play a significant role in the fragmentation of myelin basic protein (MBP) and demyelination. The splice variants of the single MBP gene are expressed in the oligodendrocytes of the central nervous system (classic MBP) and in the immune cells (Golli-MBPs). Our data suggest that persistent inflammation caused by environmental risk factors is a step to MS. We have discovered biochemical evidence suggesting the presence of the inflammatory proteolytic pathway leading to MS. The pathway involves the self-activated furin and PC2 proprotein convertases and membrane type-6 MMP (MT6-MMP/MMP-25) that is activated by furin/PC2. These events are followed by MMP-25 proteolysis of the Golli-MBP isoforms in the immune system cells and stimulation of the specific autoimmune T cell clones. It is likely that the passage of these autoimmune T cell clones through the disrupted blood-brain barrier to the brain and the recognition of neuronal, classic MBP causes inflammation leading to the further up-regulation of the activity of the multiple individual MMPs, the massive cleavage of MBP in the brain, demyelination, and MS. In addition to the cleavage of Golli-MBPs, MMP-25 proteolysis readily inactivates crystallin αB that is a suppressor of MS. These data suggest that MMP-25 plays an important role in MS pathology and that MMP-25, especially because of its restricted cell/tissue expression pattern and cell surface/lipid raft localization, is a promising drug target in MS. Multiple sclerosis (MS) is a disease of the central nervous system with autoimmune etiology. Susceptibility to MS is linked to viral and bacterial infections. Matrix metalloproteinases (MMPs) play a significant role in the fragmentation of myelin basic protein (MBP) and demyelination. The splice variants of the single MBP gene are expressed in the oligodendrocytes of the central nervous system (classic MBP) and in the immune cells (Golli-MBPs). Our data suggest that persistent inflammation caused by environmental risk factors is a step to MS. We have discovered biochemical evidence suggesting the presence of the inflammatory proteolytic pathway leading to MS. The pathway involves the self-activated furin and PC2 proprotein convertases and membrane type-6 MMP (MT6-MMP/MMP-25) that is activated by furin/PC2. These events are followed by MMP-25 proteolysis of the Golli-MBP isoforms in the immune system cells and stimulation of the specific autoimmune T cell clones. It is likely that the passage of these autoimmune T cell clones through the disrupted blood-brain barrier to the brain and the recognition of neuronal, classic MBP causes inflammation leading to the further up-regulation of the activity of the multiple individual MMPs, the massive cleavage of MBP in the brain, demyelination, and MS. In addition to the cleavage of Golli-MBPs, MMP-25 proteolysis readily inactivates crystallin αB that is a suppressor of MS. These data suggest that MMP-25 plays an important role in MS pathology and that MMP-25, especially because of its restricted cell/tissue expression pattern and cell surface/lipid raft localization, is a promising drug target in MS. MS 4The abbreviations used are: MSmultiple sclerosisBMDMbone marrow-derived macrophageCRYABcrystallin αBEAEexperimental autoimmune encephalomyelitisMBPmyelin basic proteinMMPmatrix metalloproteinasePCproprotein convertaseGAPDHglyceraldehyde-3-phosphate dehydrogenaseLPSlipopolysaccharideMALDI-TOFmatrix- assisted laser desorption ionization time-of-flightMSmass spectrometryBisTris2-[bis(2-hydroxyethyl)amino]-2-(hydroxymethyl)propane-1,3-diolRTreverse transcriptionQ-RT-PCRquantitative RT-PCRCNPase2′,3′-cyclic nucleotide 3′-phosphodiesterasedec-RVKR-cmkdecanoyl-Arg-Val-Lys-Arg-chloromethyl ketone. is a chronic, inflammatory, and T cell-mediated autoimmune disease of the central nervous system associated with demyelination, axonal loss, and brain atrophy (1Steinman L. Nat. Immunol. 2001; 2: 762-764Crossref PubMed Scopus (527) Google Scholar). Activated autoreactive T cells play a central role in MS pathophysiology. Susceptibility to MS is distantly linked to genetic variations and environmental risk factors, including vitamin D deficiency and viral and bacterial infections of the respiratory airways and gastrointestinal or urinary tracts (2Goodin D.S. PLoS ONE. 2009; 4: e4565Crossref PubMed Scopus (122) Google Scholar, 3Fugger L. Friese M.A. Bell J.I. Nat. Rev. Immunol. 2009; (in press)PubMed Google Scholar). multiple sclerosis bone marrow-derived macrophage crystallin αB experimental autoimmune encephalomyelitis myelin basic protein matrix metalloproteinase proprotein convertase glyceraldehyde-3-phosphate dehydrogenase lipopolysaccharide matrix- assisted laser desorption ionization time-of-flight mass spectrometry 2-[bis(2-hydroxyethyl)amino]-2-(hydroxymethyl)propane-1,3-diol reverse transcription quantitative RT-PCR 2′,3′-cyclic nucleotide 3′-phosphodiesterase decanoyl-Arg-Val-Lys-Arg-chloromethyl ketone. Experimental autoimmune encephalomyelitis (EAE) is an inducible disease in laboratory animals and a widely accepted model of MS. EAE is induced by autoreactive CD4+ T cells specific for myelin antigens or by immunization with myelin antigens or their peptide fragments. Proteolipid protein, myelin oligodendrocyte glycoprotein, and especially MBP are candidate autoantigens in MS. Immunoreactive MBP fragments appear in the cerebrospinal fluid in MS patients (4Hellings N. Barée M. Verhoeven C. D'hooghe M.B. Medaer R. Bernard C.C. Raus J. Stinissen P. J. Neurosci. Res. 2001; 63: 290-302Crossref PubMed Scopus (117) Google Scholar, 5Weaver A. Goncalves da Silva A. Nuttall R.K. Edwards D.R. Shapiro S.D. Rivest S. Yong V.W. FASEB J. 2005; 19: 1668-1670Crossref PubMed Scopus (130) Google Scholar). MBP and its Golli splice variants are transcribed from a single gene in humans and mice (6Campagnoni A.T. Pribyl T.M. Campagnoni C.W. Kampf K. Amur-Umarjee S. Landry C.F. Handley V.W. Newman S.L. Garbay B. Kitamura K. J. Biol. Chem. 1993; 268: 4930-4938Abstract Full Text PDF PubMed Google Scholar). There are three transcription start sites in the MBP gene. Transcription from the first site generates Golli-BG21 and -J37. The classic MBP isoforms are transcribed from the two downstream sites (7Feng J.M. Neurochem. Res. 2007; 32: 273-278Crossref PubMed Scopus (20) Google Scholar). Because of the presence of the common exons, the fragmentation of the MBP isoforms can generate similar immunogenic peptides, including the fragment of the 1–15-residue immunogenic region and a source of a dominant T cell clonotype in EAE (8Menezes J.S. van den Elzen P. Thornes J. Huffman D. Droin N.M. Maverakis E. Sercarz E.E. J. Clin. Invest. 2007; 117: 2176-2185Crossref PubMed Scopus (47) Google Scholar). The expression of the classic MBP transcripts is restricted to myelin-forming cells. BG21 and J37 are expressed in the thymus, spleen, and lymph nodes (7Feng J.M. Neurochem. Res. 2007; 32: 273-278Crossref PubMed Scopus (20) Google Scholar, 9Pribyl T.M. Campagnoni C.W. Kampf K. Kashima T. Handley V.W. McMahon J. Campagnoni A.T. Proc. Natl. Acad. Sci. U.S.A. 1993; 90: 10695-10699Crossref PubMed Scopus (184) Google Scholar) and in the myeloid lineage cells, including macrophages, dendritic cells, and granulocytes. Golli-MBPs play an incompletely understood but important role in MS (7Feng J.M. Neurochem. Res. 2007; 32: 273-278Crossref PubMed Scopus (20) Google Scholar, 10Vos C.M. van Haastert E.S. de Groot C.J. van der Valk P. de Vries H.E. J. Neuroimmunol. 2003; 138: 106-114Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar, 11Voskuhl R.R. Farris 2nd, R.W. Nagasato K. McFarland H.F. Dalcq M.D. J. Neuroimmunol. 1996; 70: 103-111Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar). Crystallin αB (CRYAB), a member of the small heat shock protein family (12van Noort J.M. van Sechel A.C. Bajramovic J.J. el Ouagmiri M. Polman C.H. Lassmann H. Ravid R. Nature. 1995; 375: 798-801Crossref PubMed Scopus (372) Google Scholar), also plays an important role in EAE acting as a brake on several inflammatory pathways in both the immune system and central nervous system. As a result, CRYAB−/− mice show worse EAE (13Ousman S.S. Tomooka B.H. van Noort J.M. Wawrousek E.F. O'Connor K.C. Hafler D.A. Sobel R.A. Robinson W.H. Steinman L. Nature. 2007; 448: 474-479Crossref PubMed Scopus (429) Google Scholar). Antibodies against CRYAB are present in the cerebrospinal fluid of MS patients and in the serum from EAE mice (14Stoevring B. Vang O. Christiansen M. Clin. Chim. Acta. 2005; 356: 95-101Crossref PubMed Scopus (26) Google Scholar). Furin, PC1/3, PC2, PC4, PC5/6, PC7, and PACE4 proprotein convertases (PCs) selectively cleave the RX(K/R/X)R sequence motif and transform inactive precursors into biologically active proteins and peptides (15Seidah N.G. Mayer G. Zaid A. Rousselet E. Nassoury N. Poirier S. Essalmani R. Prat A. Int. J. Biochem. Cell Biol. 2008; 40: 1111-1125Crossref PubMed Scopus (280) Google Scholar, 16Thomas G. Nat. Rev. Mol. Cell Biol. 2002; 3: 753-766Crossref PubMed Scopus (952) Google Scholar). PCs are synthesized as pre-proproteins in which the N-terminal prodomain functions as an autoinhibitor. To become active, PCs autoproteolytically remove the prodomain (16Thomas G. Nat. Rev. Mol. Cell Biol. 2002; 3: 753-766Crossref PubMed Scopus (952) Google Scholar). Self-activated PCs are then capable of activating the downstream proteinases, including MMPs. Because of the overlapping substrate preferences and cell/tissue expression, there is a level of redundancy in the functionality of PCs (17Scamuffa N. Calvo F. Chrétien M. Seidah N.G. Khatib A.M. FASEB J. 2006; 20: 1954-1963Crossref PubMed Scopus (188) Google Scholar, 18Remacle A.G. Shiryaev S.A. Oh E.S. Cieplak P. Srinivasan A. G. A. R. R. M. J. Biol. Chem. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar, S.A. A.G. G. M. A. R. M. R. M. M. T. M. J. Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). In for the of inflammatory cells into the central nervous to myelin and the of the blood-brain barrier 2002; PubMed Scopus Google Scholar, 2009; Full Text Full Text PDF PubMed Scopus Google Scholar). a family of that are expressed by cell especially in and are from by the and and In to these MMPs, is to the cell membrane a are synthesized as and proteolytic of the N-terminal prodomain to become active MMP-25 with the motif in its is activated by furin (16Thomas G. Nat. Rev. Mol. Cell Biol. 2002; 3: 753-766Crossref PubMed Scopus (952) Google Scholar, M. Nat. Rev. 2002; 2: PubMed Scopus Google Scholar). MMPs, the expression of MMP-25 is selectively linked to the lineage cells and in including brain A. H. R. Rev. 2008; PubMed Scopus Google Scholar). Because BG21 to the stimulation of T cells J.M. Campagnoni C.W. Campagnoni A.T. J. Neuroimmunol. Full Text Full Text PDF PubMed Scopus Google Scholar), the presence of both BG21 and MMP-25 in the raft the for the MMP-25 proteolysis of the Golli proteins in the immune system cells. that MMP-25 to of the in the MBP isoforms S.A. Cieplak P. K. PLoS ONE. 2009; 4: PubMed Scopus Google Scholar). We that MMP-25 proteolysis of the MBP isoforms with a quantitative the immunogenic N-terminal 1–15-residue peptide selectively the of the T cell from mice with EAE and specific for the 1–15-residue with MMP-25 is in the of mice with EAE induced by of T cells H. J.M. T. J. 2007; 4: PubMed Scopus Google Scholar). We that persistent inflammation caused by viral and bacterial infections is an step to both MMP-25 and Golli-MBP and to the of autoimmune MS. To that caused the up-regulation of MMP-25, and BG21 in the These events with both the specific proteolysis of BG21 of the proteolytic of CRYAB of and to the of the MBP sequence by the activated macrophages, the and of the T cell in and leading to MS. experimental suggest that persistent inflammation caused by and the proteolytic pathway in the activated cells and that these events a step to MS. As a of and because of its both restricted cell/tissue expression pattern and cell localization, have that MMP-25 is a and promising drug target in MS. from MBP from The brain protein from the brain and from the of and MS patients from the The brain from MS patients by the and The CD4+ T cell specific to fragment by for of proprotein convertases from and of from and by P. CRYAB a of Steinman against the 2′,3′-cyclic nucleotide 3′-phosphodiesterase oligodendrocyte and the against MBP from The and against the and fragments of from The to the Golli of Golli-MBP and to the PC2 and MMP-25 by and Campagnoni Pribyl T.M. J.M. Kampf K. Campagnoni C. S.D. M. Handley C. A. Campagnoni A.T. J. Neurosci. 2005; PubMed Scopus Google Scholar), of and macrophage cells in with cells in serum with from bone cells by for in a by cell cells with the MMP-25 gene in the clones and with the MMP-25 To the multiple clones and used in As a used cells with the cells with for PC2 of of expressed and from the expression system M. F. P. K. R. R. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). furin from the cell K. Shiryaev S.A. K. R. R. A.G. B. PLoS ONE. 2009; 4: PubMed Scopus Google Scholar). The BG21 and J37 Golli-MBP isoforms and CRYAB expressed in and then from the protein S.A. Cieplak P. K. PLoS ONE. 2009; 4: PubMed Scopus Google Scholar). The individual of and from The individual of and MMP-25 expressed in E. and from the in The then to their and proteolytic activity H. A. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). The of the of and from the by the cells the A. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). and activated as A. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). The of the by followed by of the The MMP used in The of the active a by against a of a or of S.A. Cieplak P. K. PLoS ONE. 2009; 4: PubMed Scopus Google Scholar, H. A. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). used as a The sequence used for the RT-PCR of PC1/3, PC2, PC5/6, and of the as and M. Seidah N. Chrétien M. Int. J. PubMed Scopus Google Scholar). The used for the of and MMP-25 of the as and are in from cells or cells for with a and then a The used in the the specific reverse and or a RT-PCR system The to their glyceraldehyde-3-phosphate dehydrogenase used as a from the cells the with and then the reverse transcription an The and the used in the with the The sequence of the is in of of and of by and to the with for and to of used to the in from in in serum in in and serum PC2 cells for then for with the followed by a with the with or The in the for the a on an with an and the brain from patients and patients with MS with the and MBP and the followed by a the system and an The and with the in the To generate the heat and the of and their of and and the data of the of of The data the and further and and the J. B. 2002; Scopus Google Scholar). The data then and gene the in to the gene to the of the data the with and of the J. B. 2002; Scopus Google Scholar). of the the gene The of then and the of the individual and CRYAB for with the individual in with and and J37 also for with furin and PC2 activity in and both with and activity to the of the that to cleave of the substrate and to the to and The cleavage a The by and MS an MS the on and of a and of a in on the target and to for with The cleavage which in the cleavage but in the and The peptide that the furin cleavage sites in the MMP-25 prodomain synthesized by The peptide for with furin or PC2 activity in and both with and The mass of the peptide and the cleavage by MS. to the to the mass of a and of an in on the target and to for To and the MMP and furin cleavage sites in the and J37 used a have and S.A. Cieplak P. K. PLoS ONE. 2009; 4: PubMed Scopus Google Scholar). to the the E. BG21 and J37 an to remove and J37 for by the individual of or for with furin of The from mice for with the As and J37 and the The CD4+ T cells specific for 1–15-residue peptide in the then to the for to the cells for The of the into the T cells by MS is by the active of the myelin in the multiple of myelin or in the central nervous system and by of and that are against myelin The of and these and show the of MBP in the active of MS The in MBP both with the presence of the macrophages, which with and with a of oligodendrocytes in the To the of MMP-25 with the bone marrow-derived lineage cells, the data of the of of of which gene of the data that to the and their and a of MMP-25 with the bone MMP-25 is the MMP that is expressed in the bone to the expression of MMP-25 in the bone marrow-derived cells, including the The three MBP isoforms and the classic MBP) readily by MMP-25 in the cleavage in The of MBP an of a the These data that MMP-25 the of the individual for the and J37 S.A. Cieplak P. K. PLoS ONE. 2009; 4: PubMed Scopus Google Scholar). to cleavage multiple MMPs, including MMP-25, capable of readily the and especially N-terminal peptides of the MBP of the These peptides similar to the immunogenic sequence of MBP that capable of EAE in M. G. T. J. J. Chem. 2008; PubMed Scopus Google Scholar, J. H. A.M. T. K. T. F. S. P. A. E. T. A. J. Chem. 2005; PubMed Scopus Google Scholar, T. S. S. T. M. S. L. A. J. J. Chem. 2002; PubMed Scopus Google Scholar). because of the cleavage redundancy MMPs, multiple individual are capable of with widely similar cleavage peptide as a of the proteolysis of the MBP and Golli-MBP To which individual MMP generates the immunogenic 1–15-residue used the to the of the T cell which is specific to the 1–15-residue fragment of MBP H. L. S.S. Steinman L. Full Text PDF PubMed Scopus Google Scholar). MBP by and The from mice with the The T cells and then to the The of the into the T cells by The and by the and then the peptides the of the specific T cells. As a used the peptide that to the sequence of MBP and the of which as The and MMP-25 of MBP in a level of of T cells with the of the suggesting a of the specific immunogenic fragment in the level of stimulation of the specific T cell the MMP-25 of BG21 used in the T cell S.A. Cieplak P. K. PLoS ONE. 2009; 4: PubMed Scopus Google Scholar). We then the activated MMPs, and their Golli-MBP To the by As by caused a of the BG21 both in the bone marrow-derived and cells RT-PCR also readily a significant in the expression of MMP-25 in the macrophages, there in individual MMPs. The of the cell and with the MMP-25 the up-regulation of MMP-25 in the macrophage cells and of PC2 and macrophage cells and the in the The cells or with The cells and with the PC2 followed by the with or with the serum The with macrophage cells in the The cells or with The cells and with the MMP-25 cells with MMP-25 or the used as cell of The with the The expression of several including PC2, and PC7, also in the and cells by RT-PCR stimulation of the cells caused an in the expression of The and the expression of PC2 the and To PC2 in addition to furin can MMP-25, the peptide that the furin cleavage site in the MMP-25 prodomain by these The MS the presence of the cleavage fragment in the cleavage that the MMP-25 activated by both furin and data that PCs PC2 and expressed MMP-25, and BG21 in the activated an for the of the cleavage pathway in the inflammatory activated the expression of BG21 in cells and also the presence of the BG21 fragments in the cells. The BG21 fragments in the cells similar to that have by MMP-25 proteolysis of the BG21 In with MMP-25, of furin are capable of the MBP isoforms in the in an of there a level of furin proteolysis of and As a result, the N-terminal immunogenic fragments of MBP The cleavage the and the mass of the peptides are in and of which are for the cleavage of suggest that in PCs to macrophage MMP-25 to the of the MBP To biochemical evidence that the activated MMP-25 and individual that cleave the MBP isoforms can the macrophage CRYAB of (13Ousman S.S. Tomooka B.H. van Noort J.M. Wawrousek E.F. O'Connor K.C. Hafler D.A. Sobel R.A. Robinson W.H. Steinman L. Nature. 2007; 448: 474-479Crossref PubMed Scopus (429) Google Scholar), the CRYAB with MMPs. The then by and also by MS to the mass the sequence of the fragments and CRYAB to proteolysis by multiple MMPs. and especially MMP-25 the of CRYAB an of the proteolytic of and As a of MMP including MMP-25 the immunogenic and fragments of CRYAB readily in the by MS proteolysis of CRYAB generates the immunogenic fragments. sequence of the crystallin αB with the and of the CRYAB and MMP The immunogenic are the of the The of these and mice and S. den R. van Noort J.M. G. J. Neuroimmunol. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, N.M. van Noort J.M. D. A. van Sechel A.C. van S. J. Neuroimmunol. Full Text Full Text PDF PubMed Scopus Google Scholar). the CRYAB cleavage by MMPs, the mass the sequence of the fragments by MS. The the of the cleavage MS is an autoimmune disease of the central nervous system. risk factors, including multiple viral and bacterial vitamin D and the appear to play a role in the of MS in MMP family to pathology in MS and EAE A.G. Yong V.W. J. Neuroimmunol. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar, A. O. J. A. P. C. A. M. C.J. Edwards D.R. C.M. C. J. Biol. Chem. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar, R. F. S. J. 2006; PubMed Scopus Google Scholar, J. C.M. L. van Haastert E.S. L. van der Valk P. de Vries H.E. 2006; 32: PubMed Scopus Google Scholar, Neurosci. 2008; PubMed Scopus Google Scholar). The data suggest that there are MMP proteolysis of demyelination, and MS 2009; Full Text Full Text PDF PubMed Scopus Google Scholar). events an MBP myelin and leading to MS. MBP generates several peptides that are (1Steinman L. Nat. Immunol. 2001; 2: 762-764Crossref PubMed Scopus (527) Google Scholar, A. T. J. D. J. F. N. M. J. M. S. Robinson W.H. F. L. Steinman L. H. 2007; PubMed Scopus Google Scholar, L. P. J. Clin. Immunol. 2001; PubMed Scopus Google Scholar, L. A. D. Mol. 1995; Full Text PDF PubMed Scopus Google Scholar, S. Steinman L. J. Clin. Invest. PubMed Scopus Google Scholar). EAE is an model of autoimmune MS. with MBP fragments autoimmune EAE in fragments of MBP are to generate EAE M. G. T. J. J. Chem. 2008; PubMed Scopus Google Scholar, J. H. A.M. T. K. T. F. S. P. A. E. T. A. J. Chem. 2005; PubMed Scopus Google Scholar, T. S. S. T. M. S. L. A. J. J. Chem. 2002; PubMed Scopus Google Scholar). There several of The expression of the classic MBP transcripts is restricted to myelin-forming cells. In the splice variants of MBP Golli-MBP BG21 and J37 (in are expressed in the thymus, spleen, and lymph nodes and in the myeloid lineage cells. Because of the presence of the common in MBP and its Golli their fragmentation can generate similar immunogenic peptides (7Feng J.M. Neurochem. Res. 2007; 32: 273-278Crossref PubMed Scopus (20) Google Scholar, 9Pribyl T.M. Campagnoni C.W. Kampf K. Kashima T. Handley V.W. McMahon J. Campagnoni A.T. Proc. Natl. Acad. Sci. U.S.A. 1993; 90: 10695-10699Crossref PubMed Scopus (184) Google Scholar). We have the biochemical evidence that the proteolysis of Golli-MBPs by MMP-25 plays a important role in the of MS. In to individual MMPs, MMP-25 is expressed in the bone and the bone marrow-derived cells, including the The of MMP-25 the furin cleavage and as a result, MMP-25 is activated by furin and to in cleavage MMP-25 is to of the in the MBP and Golli-MBP MMP-25 proteolysis of the MBP isoforms generates the immunogenic peptide sequence that selectively the of the T cell from mice with PCs furin and MMP-25, and the fragmentation of the are in the activated the that inflammation in The fragments of Golli-MBP in the similar to by MMP-25 proteolysis of the Golli-MBP the in cleavage Our data also suggest in addition to the proteolysis of MMP-25 is in a suppressor of MS (13Ousman S.S. Tomooka B.H. van Noort J.M. Wawrousek E.F. O'Connor K.C. Hafler D.A. Sobel R.A. Robinson W.H. Steinman L. Nature. 2007; 448: 474-479Crossref PubMed Scopus (429) Google Scholar). As a result, that in the of inflammation caused by environmental risk factors MMP-25 is likely to play a role as the can CRYAB in the and the of CRYAB in and the can the of the autoimmune and the for the of MS in the experimental suggest that there is a proteolytic pathway that is activated in inflammation and that the of pathway in the of viral and bacterial infections is a step to autoimmune MS We that MMP-25 plays an important role in pathway and that MMP-25, especially because of its restricted cell/tissue expression pattern and its cell surface/lipid raft localization, is a promising drug target in MS. with