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Multimodal Molecular Imaging Demonstrates Myeloperoxidase Regulation of Matrix Metalloproteinase Activity in Neuroinflammation

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Abstract

Myeloperoxidase (MPO) has paradoxically been found to be able to both activate matrix metalloproteinases (MMPs) as well as inhibit MMPs. However, these regulatory effects have not yet been observed in vivo, and it is unclear which pathway is relevant in vivo. We aim to track MPO regulation of MMP activity in living animals in neuroinflammation. Mice induced with experimental autoimmune encephalomyelitis (EAE), a mouse model of neuroinflammation and multiple sclerosis, were treated with either the MPO-specific inhibitor 4-aminobenzoic acid hydrazide or saline as control. Mice underwent concurrent magnetic resonance imaging (MRI) with the MPO-specific molecular imaging agent MPO-Gd and fluorescence molecular tomography (FMT) with the MMP-targeting agent MMPsense on day 12 after induction. Biochemical and histopathological correlations were performed. Utilizing concurrent MRI and FMT imaging, we found reduced MMP activity in the brain with MPO inhibition, demonstrating MPO activity positively regulates MMP activity in vivo. In vivo MMPSense activation and MMP-9 activity correlated with MPO-Gd+ lesion volume and disease severity. This was corroborated by in vitro assays and histopathological analyses that showed MMP activity and MMP-9+ cells correlated with MPO activity and MPO+ cells. In conclusion, multimodal molecular imaging demonstrates for the first time MPO regulation of MMP activity in living animals. This approach could serve as a model to study the interactions of other biologically interesting molecules in living organisms.

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Author notes

  1. Huateng Dong

    Present address: Department of Pediatric Neurology, Gansu Provincial Maternity and Child-Care Hospital, Lanzhou, 730050, China

  2. Yinian Zhang and Huateng Dong contributed equally to this work.

Authors and Affiliations

  1. Department of Neurosurgery, Institute of Neurology, Lanzhou University Second Hospital, 82 Cuiying Men Road, Lanzhou, 730030, China

    Yinian Zhang

  2. Center for Systems Biology and Institute for Innovation in Imaging, Department of Radiology, Harvard Medical School, Massachusetts General Hospital, 185 Cambridge Street, 5.210 Richard B. Simches Research Building, Boston, MA, 02114, USA

    Yinian Zhang, Huateng Dong, Daniel P. Seeburg, Gregory R. Wojtkiewicz, Peter Waterman, Benjamin Pulli, Reza Forghani, Muhammad Ali, Yoshiko Iwamoto, Filip K. Swirski & John W. Chen

  3. Neuroradiology Section, Charlotte Radiology, 1701 East Blvd, Charlotte, NC, 28203, USA

    Daniel P. Seeburg

  4. Department of Radiology, Jewish General Hospital and McGill University, 3755 Cote Ste-Catherine Road, Montreal, QC, Canada

    Reza Forghani

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  1. Yinian Zhang
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Correspondence to John W. Chen.

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Zhang, Y., Dong, H., Seeburg, D.P. et al. Multimodal Molecular Imaging Demonstrates Myeloperoxidase Regulation of Matrix Metalloproteinase Activity in Neuroinflammation. Mol Neurobiol 56, 954–962 (2019). https://doi.org/10.1007/s12035-018-1137-2

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  • DOI: https://doi.org/10.1007/s12035-018-1137-2

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