MMP-12, MMP-3, and TIMP-1 are markedly upregulated in chronic demyelinating theiler murine encephalomyelitis.
Theiler murine encephalomyelitis (TME) represents a highly relevant viral model for multiple sclerosis. Matrix metalloproteinases (MMPs) degrade extracellular matrix molecules and are involved in demyelination processes. To elucidate their impact on demyelination in TME, spinal cords of TME virus (TMEV)-infected SJL/J mice were taken at 9 different time points postinfection (pi) ranging from 1 hour to 196 days pi and investigated for the expression of TMEV, MMP-2, -3, -7, -9, -10, -11, -12, -13, -14, -15, -24, and TIMP-1 to -4 by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). High TMEV RNA levels were detectable throughout the observation period using RT-qPCR. In addition, TMEV RNA was visualized within demyelinated lesions by in situ hybridization. MMP-3 mRNA was significantly upregulated at 1 day pi and again in the late phase of infection. TIMP-1 mRNA was significantly elevated throughout the observation period. MMP-12 mRNA was most prominently upregulated in the late phase of infection and MMP-12 protein was localized in intralesional microglia/macrophages and astrocytes by immunohistochemistry. In summary, in early TMEV infection, MMP-3 and TIMP-1 mRNA upregulation might be directly virus-induced, whereas persistent TMEV infection directly or indirectly stimulated MMP-12 production in microglia/macrophages and astrocytes and might account for ongoing demyelination in TME.
Ulrich
Reiner
R
Department of Pathology, University of Veterinary Medicine Hannover, Germany.
Baumgärtner
Wolfgang
W
Gerhauser
Ingo
I
Seeliger
Frank
F
Haist
Verena
V
Deschl
Ulrich
U
Alldinger
Susanne
S
D000818:Animals; D018188:Cardiovirus Infections / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002490:Central Nervous System / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D002908:Chronic Disease; D003711:Demyelinating Diseases / Q000201:enzymology* / Q000235:genetics / Q000821:virology; D004195:Disease Models, Animal; D004679:Encephalomyelitis / Q000201:enzymology* / Q000235:genetics / Q000821:virology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D008264:Macrophages / Q000378:metabolism; D053508:Matrix Metalloproteinase 12; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D008666:Metalloendopeptidases / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000378:metabolism; D009103:Multiple Sclerosis / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D009186:Myelin Sheath / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D012367:RNA, Viral / Q000032:analysis / Q000235:genetics; D017945:Theilovirus / Q000235:genetics*; D013997:Time Factors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism*; D015854:Up-Regulation; D019562:Viral Load
D012333:RNA, Messenger; D012367:RNA, Viral; D019715:Tissue Inhibitor of Metalloproteinase-1; D020782:Matrix Metalloproteinases; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3; D053508:Matrix Metalloproteinase 12