The Journal of Experimental Medicine
Avanti Polar Lipids
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Published online March 5, 2007
doi:10.1084/jem.20061931
The Journal of Experimental Medicine, Vol. 204, No. 3, 571-582
The Rockefeller University Press, 0022-1007 $30.00
© 2007 Adams et al.
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ARTICLE

 The fibrin-derived {gamma}377-395 peptide inhibits microglia activation and suppresses relapsing paralysis in central nervous system autoimmune disease

Ryan A. Adams1, Jan Bauer2, Matthew J. Flick3, Shoana L. Sikorski1, Tal Nuriel1, Hans Lassmann2, Jay L. Degen3, and Katerina Akassoglou1

1 Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093
2 Center for Brain Research, Medical University of Vienna, A-1090 Vienna, Austria
3 Children's Hospital Research Foundation and the University of Cincinnati College of Medicine, Cincinnati, OH 45229

CORRESPONDENCE Katerina Akassoglou: akass{at}ucsd.edu

Perivascular microglia activation is a hallmark of inflammatory demyelination in multiple sclerosis (MS), but the mechanisms underlying microglia activation and specific strategies to attenuate their activation remain elusive. Here, we identify fibrinogen as a novel regulator of microglia activation and show that targeting of the interaction of fibrinogen with the microglia integrin receptor Mac-1 ({alpha}Mß2, CD11b/CD18) is sufficient to suppress experimental autoimmune encephalomyelitis in mice that retain full coagulation function. We show that fibrinogen, which is deposited perivascularly in MS plaques, signals through Mac-1 and induces the differentiation of microglia to phagocytes via activation of Akt and Rho. Genetic disruption of fibrinogen–Mac-1 interaction in fibrinogen-{gamma}390-396A knock-in mice or pharmacologically impeding fibrinogen–Mac-1 interaction through intranasal delivery of a fibrinogen-derived inhibitory peptide ({gamma}377-395) attenuates microglia activation and suppresses relapsing paralysis. Because blocking fibrinogen–Mac-1 interactions affects the proinflammatory but not the procoagulant properties of fibrinogen, targeting the {gamma}377-395 fibrinogen epitope could represent a potential therapeutic strategy for MS and other neuroinflammatory diseases associated with blood-brain barrier disruption and microglia activation.

Abbreviations used: BBB, blood-brain barrier; CNS, central nervous system; EAE, experimental autoimmune encephalomyelitis; iNOS, inducible nitric oxide synthase; MOG, myelin oligodendrocyte glycoprotein; MS, multiple sclerosis; PI3K, phosphoinositide 3-kinase; PLP, proteolipid protein; TLR, Toll-like receptor.

T. Nuriel's present address is Weill Medical School of Cornell University, New York, NY 10021.


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