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, Katerina Akassoglou

Research output: Contribution to journalArticle

Abstract

Clearance of fibrin through proteolytic degradation is a critical step of matrix remodeling that contributes to tissue repair in a variety of pathological conditions, such as stroke, atherosclerosis, and pulmonary disease. However, the molecular mechanisms that regulate fibrin deposition are not known. Here, we report that the p75 neurotrophin receptor (p75NTR), a TNF receptor superfamily member up-regulated after tissue injury, blocks fibrinolysis by down-regulating the serine protease, tissue plasminogen activator (tPA), and upregulating plasminogen activator inhibitor-1 (PAI-1). We have discovered a new mechanism in which phosphodiesterase PDE4A4/5 interacts with p75NTR to enhance cAMP degradation. The p75NTR-dependent down-regulation of cAMP results in a decrease in extracellular proteolytic activity. This mechanism is supported in vivo in p75NTR-defi cient mice, which show increased proteolysis after sciatic nerve injury and lung fibrosis. Our results reveal a novel pathogenic mechanism by which p75NTR regulates degradation of cAMP and perpetuates scar formation after injury.

Original languageEnglish (US)
Pages (from-to)1119-1132
Number of pages14
JournalJournal of Cell Biology
Volume177
Issue number6
DOIs
StatePublished - Jun 18 2007

ASJC Scopus subject areas

  • Cell Biology

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    Sachs, B. D., Baillie, G. S., McCall, J. R., Passino, M. A., Schachtrup, C., Wallace, D. A., Dunlop, A. J., MacKenzie, K. F., Klussmann, E., Lynch, M. J., Sikorski, S. L., Nuriel, T., Tsigelny, I., Zhang, J., Houslay, M. D., Chao, M. V., & Akassoglou, K. (2007). p75 neurotrophin receptor regulates tissue fibrosis through inhibition of plasminogen activation via a PDE4/cAMP/PKA pathway. Journal of Cell Biology, 177(6), 1119-1132. https://doi.org/10.1083/jcb.200701040