Imaging matrix metalloproteinase activity in multiple sclerosis as a specific marker of leukocyte penetration of the blood-brain barrier.
The enzymes gelatinase A/matrix metalloproteinase-2 (MMP-2) and gelatinase B/MMP-9 are essential for induction of neuroinflammatory symptoms in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS); in the absence of these enzymes, the disease does not develop. We therefore investigated the cellular sources and relative contributions of MMP-2 and MMP-9 to disease at early stages of EAE induction. We demonstrated that MMP-9 from an immune cell source is required in EAE for initial infiltration of leukocytes into the central nervous system and that MMP-9 activity is a reliable marker of leukocyte penetration of the blood-brain barrier. We then developed a molecular imaging method to visualize MMP activity in the brain using fluorescent- and radioactive-labeled MMP inhibitors (MMPis) in EAE animals and used the radioactive MMP ligand for positron emission tomography (PET) imaging of MMP activity in patients with MS. In contrast to traditional T1-gadolinium contrast-enhanced MRI, MMPi-PET enabled tracking of MMP activity as a unique feature of early lesions and ongoing leukocyte infiltration. MMPi-PET therefore allows monitoring of the early steps of MS development and provides a sensitive, noninvasive means of following lesion formation and resolution in murine EAE and human MS.
Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, DE-48149 Münster, Germany.|Cells-in-Motion Cluster of Excellence, University of Münster, DE-48149 Münster, Germany.
Hanna
H
Gerwien
Cells-in-Motion Cluster of Excellence, University of Münster, DE-48149 Münster, Germany.|European Institute for Molecular Imaging, University of Münster, DE-48149 Münster, Germany.
Sven
S
Hermann
Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, DE-48149 Münster, Germany.|Cells-in-Motion Cluster of Excellence, University of Münster, DE-48149 Münster, Germany.
Xueli
X
Zhang
Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, DE-48149 Münster, Germany.|Cells-in-Motion Cluster of Excellence, University of Münster, DE-48149 Münster, Germany.
Eva
E
Korpos
Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, DE-48149 Münster, Germany.|Cells-in-Motion Cluster of Excellence, University of Münster, DE-48149 Münster, Germany.
Jian
J
Song
Department of Nuclear Medicine, University of Münster, DE-48149 Münster, Germany.
Klaus
K
Kopka
Cells-in-Motion Cluster of Excellence, University of Münster, DE-48149 Münster, Germany.|European Institute for Molecular Imaging, University of Münster, DE-48149 Münster, Germany.
Andreas
A
Faust
Department of Nuclear Medicine, University of Münster, DE-48149 Münster, Germany.
Christian
C
Wenning
Cells-in-Motion Cluster of Excellence, University of Münster, DE-48149 Münster, Germany.|Department of Neurology, University of Münster, DE-48149 Münster, Germany.
Catharina C
CC
Gross
European Institute for Molecular Imaging, University of Münster, DE-48149 Münster, Germany.
Lisa
L
Honold
Department of Neurology, University of Münster, DE-48149 Münster, Germany.
Nico
N
Melzer
Rega Institute for Medical Research, Department of Microbiology and Immunology, University of Leuven, BE-3000 Leuven, Belgium.
Ghislain
G
Opdenakker
Cells-in-Motion Cluster of Excellence, University of Münster, DE-48149 Münster, Germany.|Department of Neurology, University of Münster, DE-48149 Münster, Germany.
Heinz
H
Wiendl
Cells-in-Motion Cluster of Excellence, University of Münster, DE-48149 Münster, Germany.|European Institute for Molecular Imaging, University of Münster, DE-48149 Münster, Germany.|Department of Nuclear Medicine, University of Münster, DE-48149 Münster, Germany.
Michael
M
Schäfers
Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, DE-48149 Münster, Germany.|Cells-in-Motion Cluster of Excellence, University of Münster, DE-48149 Münster, Germany.
Lydia
L
Sorokin
D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007107:Immune System; D007249:Inflammation; D007962:Leukocytes / Q000166:cytology*; D008024:Ligands; D008279:Magnetic Resonance Imaging; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009103:Multiple Sclerosis / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology*; D049268:Positron-Emission Tomography; D013116:Spinal Cord / Q000378:metabolism
D008024:Ligands; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse