The fibrin (red) that blocks nerve healing is degraded when p75NTR isn't around (right) to dampen tPA levels.
Tissue scars are formed from build-ups of extracellular matrix proteins. In particular, a blood-clotting factor called fibrin escapes from damaged vessels and is deposited as a temporary matrix in the tissue. The deposits can block nerve regeneration and cause lung and vascular diseases.
Fibrin's degradation by plasmin allows healing to proceed more efficiently. Sachs and colleagues thus went looking for factors that either block or help this degradation. They had noticed that fibrin deposits were often found in areas with high levels of the TNF receptor family member, p75NTR. Although usually associated with the nervous system, where it mainly activates apoptosis, p75NTR is also expressed in the liver and lung upon injury.
Mice lacking p75NTR now reveal that this death receptor prevents fibrin degradation. The mutant mice had less fibrin deposition upon nerve injury than did injured normal mice. Revved up plasmin activity accounted for the better degradation in the mutants. Plasmin can be turned on by two activators, tPA and uPA, but only tPA levels were higher in the mutants.
The gene for tPA is induced by cAMP signaling, which the authors found is dampened by p75NTR. They identified a binding site in the receptor for a specific phosphodiesterase that targets cAMP degradation to the membrane. Although p75NTR also binds to neurotrophins, these extracellular ligands were not necessary for cAMP degradation. Receptor expression and recruitment of the phosphodiesterase seem to be enough.
tPA is the drug used immediately following strokes to prevent lasting brain damage. The drug Rolipram also reduces fibrosis, via its broad-scale inhibition of phosphodiesterases. Both have unwanted side effects, however. A better, more specific strategy to boost cAMP levels and fibrinolysis might be to interfere with the interaction of p75NTR and its particular phosphodiesterase partner. 
