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Proteomic analysis of active multiple sclerosis lesions reveals therapeutic targets

Abstract

Understanding the neuropathology of multiple sclerosis (MS) is essential for improved therapies. Therefore, identification of targets specific to pathological types of MS may have therapeutic benefits. Here we identify, by laser-capture microdissection and proteomics, proteins unique to three major types of MS lesions: acute plaque, chronic active plaque and chronic plaque. Comparative proteomic profiles identified tissue factor and protein C inhibitor within chronic active plaque samples, suggesting dysregulation of molecules associated with coagulation. In vivo administration of hirudin or recombinant activated protein C reduced disease severity in experimental autoimmune encephalomyelitis and suppressed Th1 and Th17 cytokines in astrocytes and immune cells. Administration of mutant forms of recombinant activated protein C showed that both its anticoagulant and its signalling functions were essential for optimal amelioration of experimental autoimmune encephalomyelitis. A proteomic approach illuminated potential therapeutic targets selective for specific pathological stages of MS and implicated participation of the coagulation cascade.

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Figure 1: Histopathology of MS brain lesions.
Figure 2: Proteomic analysis of MS lesions.
Figure 3: Thrombin inhibition suppresses inflammation in EAE.
Figure 4: aPC modulates Th1 and Th17 responses in EAE.
Figure 5: Molecular mechanism of aPC during EAE.

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Acknowledgements

We thank Mary Jane Eaton for help with histopathology and Jian Luo for help with imaging microscopy. This work was funded by the National Institutes of Health and the National Multiple Sclerosis Society to L.S., the National Institutes of Health to D.H., and Ruth L. Kirschstein National Research Service Award and T32 Adult and Pediatric Rheumatology and Immunology Fellowship awards to M.H.H. B.W.G. and B.G. are employed by Lilly Research Laboratories, a division of Eli Lilly & Co.

Author Contributions M.H.H. and L.S. formulated the hypothesis and designed all the experiments. D.K.H., S.-I.H. and D.H.L. contributed the proteomic studies. D.B.R. performed the EAE experiment with hirudin treatment. R.A.S. and C.S.R. contributed to the histopathological analysis. B.G. and B.W.G. provided the recombinant aPC proteins. J.V.P. performed studies on NF-κB signalling. S.S.O. performed the in vitro assays with astrocytes. D.K.H. and L.S., the senior authors, contributed equally to this work.

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Correspondence to Lawrence Steinman.

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Brian W. Grinnell and Bruce Gerlitz are employees of Eli Lilly.

Supplementary information

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Han, M., Hwang, SI., Roy, D. et al. Proteomic analysis of active multiple sclerosis lesions reveals therapeutic targets. Nature 451, 1076–1081 (2008). https://doi.org/10.1038/nature06559

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