title: p75 neurotrophin receptor regulates tissue fibrosis through inhibition of plasminogen activation via a PDE4/cAMP/PKA pathway.
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 (p75(NTR)), a TNF receptor superfamily member up-regulated after tissue injury, blocks fibrinolysis by down-regulating the serine protease, tissue plasminogen activator (tPA), and up-regulating plasminogen activator inhibitor-1 (PAI-1). We have discovered a new mechanism in which phosphodiesterase PDE4A4/5 interacts with p75(NTR) to enhance cAMP degradation. The p75(NTR)-dependent down-regulation of cAMP results in a decrease in extracellular proteolytic activity. This mechanism is supported in vivo in p75(NTR)-deficient mice, which show increased proteolysis after sciatic nerve injury and lung fibrosis. Our results reveal a novel pathogenic mechanism by which p75(NTR) regulates degradation of cAMP and perpetuates scar formation after injury.
authors.affiliation: Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Sachs
authors.forename: George S
authors.initials: GS
authors.lastname: Baillie
authors.forename: Julianne R
authors.initials: JR
authors.lastname: McCall
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Passino
authors.forename: Christian
authors.initials: C
authors.lastname: Schachtrup
authors.forename: Derek A
authors.initials: DA
authors.lastname: Wallace
authors.forename: Allan J
authors.initials: AJ
authors.lastname: Dunlop
authors.forename: Kirsty F
authors.initials: KF
authors.lastname: MacKenzie
authors.forename: Enno
authors.initials: E
authors.lastname: Klussmann
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Lynch
authors.forename: Shoana L
authors.initials: SL
authors.lastname: Sikorski
authors.forename: Tal
authors.initials: T
authors.lastname: Nuriel
authors.forename: Igor
authors.initials: I
authors.lastname: Tsigelny
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.forename: Miles D
authors.initials: MD
authors.lastname: Houslay
authors.forename: Moses V
authors.initials: MV
authors.lastname: Chao
authors.forename: Katerina
authors.initials: K
authors.lastname: Akassoglou
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism*; D000818:Animals; D002921:Cicatrix / Q000209:etiology; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D005342:Fibrinolysis; D005355:Fibrosis; D005786:Gene Expression Regulation; D051379:Mice; D018345:Mice, Knockout; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D020800:Receptor, Nerve Growth Factor / Q000502:physiology*; D012584:Sciatic Nerve / Q000293:injuries; D010959:Tissue Plasminogen Activator / Q000037:antagonists & inhibitors*; D014947:Wounds and Injuries
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D020800:Receptor, Nerve Growth Factor; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D010959:Tissue Plasminogen Activator