Retinal neurons curb inflammation and enhance revascularization in ischemic retinopathies via proteinase-activated receptor-2.
Am J Pathol
; 185(2): 581-95, 2015 Feb.
Article
en En
| MEDLINE
| ID: mdl-25478809
ABSTRACT
Ischemic retinopathies are characterized by sequential vaso-obliteration followed by abnormal intravitreal neovascularization predisposing patients to retinal detachment and blindness. Ischemic retinopathies are associated with robust inflammation that leads to generation of IL-1ß, which causes vascular degeneration and impairs retinal revascularization in part through the liberation of repulsive guidance cue semaphorin 3A (Sema3A). However, retinal revascularization begins as inflammation culminates in ischemic retinopathies. Because inflammation leads to activation of proteases involved in the formation of vasculature, we hypothesized that proteinase-activated receptor (Par)-2 (official name F2rl1) may modulate deleterious effects of IL-1ß. Par2, detected mostly in retinal ganglion cells, was up-regulated in oxygen-induced retinopathy. Surprisingly, oxygen-induced retinopathy-induced vaso-obliteration and neovascularization were unaltered in Par2 knockout mice, suggesting compensatory mechanisms. We therefore conditionally knocked down retinal Par2 with shRNA-Par2-encoded lentivirus. Par2 knockdown interfered with normal revascularization, resulting in pronounced intravitreal neovascularization; conversely, the Par2 agonist peptide (SLIGRL) accelerated normal revascularization. In vitro and in vivo exploration of mechanisms revealed that IL-1ß induced Par2 expression, which in turn down-regulated sequentially IL-1 receptor type I and Sema3A expression through Erk/Jnk-dependent processes. Collectively, our findings unveil an important mechanism by which IL-1ß regulates its own endothelial cytotoxic actions by augmenting neuronal Par2 expression to repress sequentially IL-1 receptor type I and Sema3A expression. Timely activation of Par2 may be a promising therapeutic avenue in ischemic retinopathies.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Enfermedades de la Retina
/
Receptores de Trombina
/
Proteínas del Ojo
/
Neuronas Retinianas
/
Isquemia
Tipo de estudio:
Guideline
Límite:
Animals
Idioma:
En
Revista:
Am J Pathol
Año:
2015
Tipo del documento:
Article
País de afiliación:
Canadá