p75 neurotrophin receptor regulates tissue fibrosis through inhibition of plasminogen activation via a PDE4/cAMP/PKA pathway.
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.
Sachs
Benjamin D
BD
Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA.
Baillie
George S
GS
McCall
Julianne R
JR
Passino
Melissa A
MA
Schachtrup
Christian
C
Wallace
Derek A
DA
Dunlop
Allan J
AJ
MacKenzie
Kirsty F
KF
Klussmann
Enno
E
Lynch
Martin J
MJ
Sikorski
Shoana L
SL
Nuriel
Tal
T
Tsigelny
Igor
I
Zhang
Jin
J
Houslay
Miles D
MD
Chao
Moses V
MV
Akassoglou
Katerina
K
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
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