An elevated matrix metalloproteinase (MMP) in an animal model of multiple sclerosis is protective by affecting Th1/Th2 polarization.
Inflammation in multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), is manifested by changes in matrix metalloproteinase (MMP) expression and in the ratio of T helper (Th) 1 and 2 effector cytokines. Here, we provide a comprehensive documentation of MMPs in EAE and report that of all the MMPs that could be measured at peak disease in spinal cord tissue, MMP-12 was the most highly up-regulated. In contrast to previously published findings of MMPs in EAE, this increase in MMP-12 expression was associated with protection, as MMP-12 null mice had significantly worse maximum severity and EAE disease burden compared with wild-type (WT) controls. When spleen and lymph node cells were removed from EAE-afflicted WT and MMP-12 null mice at the same disease score before divergence of disease and restimulated in vitro, the MMP-12 null cells had significantly higher Th1 to Th2 cytokine ratio. Measurements of the transcriptional regulators of T cell polarization revealed that MMP-12 null cells had increased T-bet and reduced GATA-3 expression, a condition that favors a Th1 bias. These results emphasize that specific MMPs can have beneficial roles in inflammation, and they implicate MMPs in T effector polarization for the first time.
Weaver
Andrew
A
University of Calgary, Calgary, Alberta, Canada.
Goncalves da Silva
Angelika
A
Nuttall
Robert K
RK
Edwards
Dylan R
DR
Shapiro
Steven D
SD
Rivest
Serge
S
Yong
V Wee
VW
D000818:Animals; D015551:Autoimmunity; D016207:Cytokines / Q000378:metabolism; D018450:Disease Progression; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000201:enzymology; D005260:Female; D005786:Gene Expression Regulation; D007249:Inflammation; D008198:Lymph Nodes / Q000473:pathology; D053508:Matrix Metalloproteinase 12; D008666:Metalloendopeptidases / Q000096:biosynthesis*; D051379:Mice; D008954:Models, Biological; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000737:chemistry; D063308:Myelin-Oligodendrocyte Glycoprotein; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013116:Spinal Cord / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D013601:T-Lymphocytes / Q000378:metabolism; D018417:Th1 Cells / Q000166:cytology* / Q000378:metabolism; D018418:Th2 Cells / Q000166:cytology* / Q000378:metabolism; D014158:Transcription, Genetic; D016896:Treatment Outcome; D015854:Up-Regulation
D016207:Cytokines; C571327:Mog protein, mouse; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D012333:RNA, Messenger; D012313:RNA; D008666:Metalloendopeptidases; D053508:Matrix Metalloproteinase 12