The Journal of Experimental Medicine
Fluorescence In Vivo Endomicroscopy
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Published online 13 February 2006 doi:10.1084/jem.20052148
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 2, 425-435
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ARTICLE

 Proteinase-activated receptor 2 modulates neuroinflammation in experimental autoimmune encephalomyelitis and multiple sclerosis

Farshid Noorbakhsh1,3,6, Shigeki Tsutsui2,3, Nathalie Vergnolle4, Leonie A. Boven5, Neda Shariat1, Mohammed Vodjgani6, Kenneth G. Warren1, Patricia Andrade-Gordon7, Morley D. Hollenberg4, and Christopher Power1,3

1 Department of Medicine, University of Alberta, Edmonton, Alberta T6G 2S2, Canada
2 Department of Biochemistry & Molecular Biology, 3 Department of Clinical Neurosciences, and 4 Department of Pharmacology & Therapeutics, University of Calgary, Calgary, Alberta T2N 1N4, Canada
5 Department of Immunology, Erasmus Medical Center, 3000 DR Rotterdam, Netherlands
6 Department of Immunology, Tehran University of Medical Sciences, 1417613151 Tehran, Iran
7 Johnson & Johnson Pharmaceutical Research and Development, Spring House, PA 19477

CORRESPONDENCE Christopher Power: chris.power{at}ualberta.ca

The proteinase-activated receptors (PARs) are widely recognized for their modulatory properties of inflammation and neurodegeneration. We investigated the role of PAR2 in the pathogenesis of multiple sclerosis (MS) in humans and experimental autoimmune encephalomyelitis (EAE) in mice. PAR2 expression was increased on astrocytes and infiltrating macrophages in human MS and murine EAE central nervous system (CNS) white matter (P < 0.05). Macrophages and astrocytes from PAR2 wild-type (WT) and knockout (KO) mice exhibited differential immune gene expression with PAR2 KO macrophages showing significantly higher interleukin 10 production after lipopolysaccharide stimulation (P < 0.001). PAR2 activation in macrophages resulted in the release of soluble oligodendrocyte cytotoxins (P < 0.01). Myelin oligodendrocyte glycoprotein–induced EAE caused more severe inflammatory gene expression in the CNS of PAR2 WT animals (P < 0.05), together with enhanced T cell proliferation and interferon {gamma} production (P < 0.05), compared with KO littermates. Indeed, PAR2 WT animals showed markedly greater microglial activation and T lymphocyte infiltration accompanied by worsened demyelination and axonal injury in the CNS compared with their PAR2 KO littermates. Enhanced neuropathological changes were associated with a more severe progressive relapsing disease phenotype (P < 0.001) in WT animals. These findings reveal previously unreported pathogenic interactions between CNS PAR2 expression and neuroinflammation with ensuing demyelination and axonal injury.

Abbreviations used: CNS, central nervous system(s); EAE, experimental autoimmune encep-halomyelitis; GFAP, glial fibrillary acidic protein; Iba-1, ionized calcium binding adaptor protein; iNOS, inducible nitric oxide syn-thase; mAP, mutant inactive peptide; MBP, myelin basic protein; MOG, myelin oligodendrocyte glycoprotein; MS, multiple sclerosis; PAR, proteinase-activated receptor; PAR2 AP, PAR2-activating peptide.


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