Fibrin depletion decreases inflammation and delays the onset of demyelination in a tumor necrosis factor transgenic mouse model for multiple sclerosis

doi:10.1073/pnas.0303859101

Fibrin depletion decreases inflammation and delays the onset of demyelination in a tumor necrosis factor transgenic mouse model for multiple sclerosis

^*Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093-0636; ^†Laboratory of Neurobiology and Genetics, The Rockefeller University, New York, NY 10021; ^¶Laboratory of Experimental Neuropathology, University of Vienna, A-1090 Vienna, Austria; and ^∥Laboratory of Molecular Genetics, Hellenic Pasteur Institute, 127 Vassilissis Sofias Avenue, Athens 11521, Greece

Edited by Anthony Cerami, The Kenneth S. Warren Institute, Kitchawan, NY, and approved March 4, 2004 (received for review June 20, 2003)

Abstract

In multiple sclerosis, in which brain tissue becomes permeable to blood proteins, extravascular fibrin deposition correlates with sites of inflammatory demyelination and axonal damage. To examine the role of fibrin in neuroinflammatory demyelination, we depleted fibrin in two tumor necrosis factor transgenic mouse models of multiple sclerosis, transgenic lines TgK21 and Tg6074. In a genetic analysis, we crossed TgK21 mice into a fibrin-deficient background. TgK21fib ^-/- mice had decreased inflammation and expression of major histocompatibility complex class I antigens, reduced demyelination, and a lengthened lifespan compared with TgK21 mice. In a pharmacologic analysis, fibrin depletion, by using the snake venom ancrod, in Tg6074 mice also delayed the onset of inflammatory demyelination. Overall, these results indicate that fibrin regulates the inflammatory response in neuroinflammatory diseases. Design of therapeutic strategies based on fibrin depletion could potentially benefit the clinical course of demyelinating diseases such as multiple sclerosis.

Footnotes

↵ ‡ To whom correspondence should be addressed at: Department of Pharmacology, BSB, Room 3040, University of California at San Diego, La Jolla, CA 92093-0636. E-mail: akass{at}ucsd.edu.
↵ § R.A.A. and J.B. contributed equally to this work.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: BBB, blood-brain barrier; EAE, experimental autoimmune encephalomyelitis; LPS, lipopolysaccharide; MS, multiple sclerosis; TNF, tumor necrosis factor.