title: Retinal neurons curb inflammation and enhance revascularization in ischemic retinopathies via proteinase-activated receptor-2.
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-1β, 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-1β. 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-1β 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-1β 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.
authors.affiliation: Department of Pharmacology, CHU Sainte-Justine Hospital, University of Montréal, Montréal, Québec, Canada; Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Center, University of Montréal, Montréal, Québec, Canada.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Sitaras
authors.affiliation: Department of Pharmacology, CHU Sainte-Justine Hospital, University of Montréal, Montréal, Québec, Canada; Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Center, University of Montréal, Montréal, Québec, Canada. Electronic address: jc.rivera@umontreal.ca.
authors.forename: José Carlos
authors.initials: JC
authors.lastname: Rivera
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada.
authors.forename: Baraa
authors.initials: B
authors.lastname: Noueihed
authors.affiliation: Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Center, University of Montréal, Montréal, Québec, Canada.
authors.forename: Milsa
authors.initials: M
authors.lastname: Bien-Aimé
authors.affiliation: LOEX-CUO Research Center, Saint-Sacrement Hospital, Québec, Québec, Canada.
authors.forename: Karine
authors.initials: K
authors.lastname: Zaniolo
authors.affiliation: Department of Pharmacology, CHU Sainte-Justine Hospital, University of Montréal, Montréal, Québec, Canada; Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Center, University of Montréal, Montréal, Québec, Canada.
authors.forename: Samy
authors.initials: S
authors.lastname: Omri
authors.affiliation: Department of Pharmacology, CHU Sainte-Justine Hospital, University of Montréal, Montréal, Québec, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Hamel
authors.affiliation: Department of Pharmacology, CHU Sainte-Justine Hospital, University of Montréal, Montréal, Québec, Canada.
authors.forename: Tang
authors.initials: T
authors.lastname: Zhu
authors.affiliation: Department of Pediatrics, CHU Sainte-Justine Hospital, University of Montréal, Montréal, Québec, Canada.
authors.forename: Pierre
authors.initials: P
authors.lastname: Hardy
authors.affiliation: Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Center, University of Montréal, Montréal, Québec, Canada.
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Sapieha
authors.affiliation: Department of Pharmacology, CHU Sainte-Justine Hospital, University of Montréal, Montréal, Québec, Canada; Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada; Department of Pediatrics, CHU Sainte-Justine Hospital, University of Montréal, Montréal, Québec, Canada. Electronic address: js.joyal@umontreal.ca.
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Joyal
authors.affiliation: Department of Pharmacology, CHU Sainte-Justine Hospital, University of Montréal, Montréal, Québec, Canada; Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Center, University of Montréal, Montréal, Québec, Canada; Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada; Department of Pediatrics, CHU Sainte-Justine Hospital, University of Montréal, Montréal, Québec, Canada. Electronic address: sylvain.chemtob@umontreal.ca.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Chemtob
mesh_terms: D000818:Animals; D005136:Eye Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D007511:Ischemia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009842:Oligopeptides / Q000494:pharmacology; D018179:Receptors, Thrombin / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D012164:Retinal Diseases / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D055351:Retinal Neurons / Q000378:metabolism* / Q000473:pathology; D040121:Semaphorin-3A / Q000235:genetics / Q000378:metabolism
chemical_list: D005136:Eye Proteins; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D009842:Oligopeptides; D018179:Receptors, Thrombin; C488217:Sema3a protein, mouse; D040121:Semaphorin-3A; C105295:protease-activated receptor 3; C099570:seryl-leucyl-isoleucyl-glycyl-arginyl-leucine