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The fibrin (red) that blocks nerve healing is degraded when p75NTR isn't around (right) to dampen tPA levels.

Even when it's not killing, a death receptor still finds ways to inflict damage. On page 1119, Sachs et al. show that a TNF receptor helps build scars that can get in the way of healing.

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, p75^NTR. Although usually associated with the nervous system, where it mainly activates apoptosis, p75^NTR is also expressed in the liver and lung upon injury.

Mice lacking p75^NTR 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 p75^NTR. They identified a binding site in the receptor for a specific phosphodiesterase that targets cAMP degradation to the membrane. Although p75^NTR 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 p75^NTR and its particular phosphodiesterase partner.

Nicole LeBrasseur

lebrasn{at}rockefeller.edu

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p75 neurotrophin receptor regulates tissue fibrosis through inhibition of plasminogen activation via a PDE4/cAMP/PKA pathway

Benjamin D. Sachs, George S. Baillie, Julianne R. McCall, Melissa A. Passino, Christian Schachtrup, Derek A. Wallace, Allan J. Dunlop, Kirsty F. MacKenzie, Enno Klussmann, Martin J. Lynch, Shoana L. Sikorski, Tal Nuriel, Igor Tsigelny, Jin Zhang, Miles D. Houslay, Moses V. Chao, and Katerina Akassoglou
J. Cell Biol. 2007 177: 1119-1132. [Abstract] [Full Text] [PDF]

This Article PDF (Full Text) PPT slides of all figures Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by LeBrasseur, N. Search for Related Content PubMed Articles by LeBrasseur, N. Related Collections Related Article Social Bookmarking                      What's this?