Microglial activation (left) is prevented by blocking fibrin (right).

The neurological dysfunction seen in MS is caused by the destruction of myelin sheaths around axons. This destruction is thought to be driven by T helper (Th)-1 cells, and most of the current treatment protocols are focused on inhibiting their activation and entry into the CNS. But responses to anti–T cell therapy are variable, and inflammatory demyelination can sometimes occur in the absence of T cells.

One feature that all MS lesions have in common is a disruption in the blood–brain barrier and the leakage of fibrinogen into the brain through the damaged endothelia. This results in the formation of fibrin deposits, which are detected even before demyelination. These deposits also overlap with regions where resting microglia have differentiated into phagocytic cells that damage myelin, raising the possibility that clotting proteins activate microglia.

Akassoglou and colleagues had previously shown that fibrinogen promotes disease in mouse models of MS. The team now shows that fibrinogen binds to a macrophage-activating receptor called Mac-1 that is expressed by local microglial cells.

Mice expressing a mutant form of fibrinogen that fails to bind Mac-1 had fewer inflammatory lesions and less severe disease. Blocking the fibrinogen–Mac-1 interaction with an antagonist peptide prevented relapses and further myelin damage in diseased mice and allowed these animals to survive with improved motor function.

Fibrinogen is an attractive target for MS therapy as its appearance in the brain is an early sign of neurodegeneration. Current methods to target fibrinogen involve the use of anticoagulants, but their long-term use increases the risk of hemorrhage. The region of fibrinogen that promotes clotting is, however, distinct from its Mac-1–activating site. Specifically targeting the latter interaction might therefore be a safer option in MS therapy, although it is not yet clear whether T cell–dependent pathways would also need to be blocked.