title: Microglia and interleukin-1β in ischemic retinopathy elicit microvascular degeneration through neuronal semaphorin-3A.
abstract: OBJECTIVE
  Proinflammatory cytokines contribute to the development of retinal vasculopathies. However, the role of these factors and the mechanisms by which they elicit their effects in retina are not known. We investigated whether activated microglia during early stages of ischemic retinopathy produces excessive interleukin-1β (IL-1β), which elicits retinal microvascular degeneration not directly but rather by triggering the release of the proapoptotic/repulsive factor semaphorin-3A (Sema3A) from neurons.
  
  
  RESULTS
  Sprague Dawley rats subjected to retinopathy induced by hyperoxia (80% O2; O2-induced retinopathy) exhibited retinal vaso-obliteration associated with microglial activation, NLRP3 upregulation, and IL-1β and Sema3A release; IL-1β was mostly generated by microglia. Intraperitoneal administration of IL-1 receptor antagonists (Kineret, or rytvela [101.10]) decreased these effects and enhanced retinal revascularization; knockdown of Sema3A resulted in microvessel preservation and, conversely, administration of IL-1β caused vaso-obliteration. In vitro, IL-1β derived from activated primary microglial cells, cultured under hyperoxia, stimulated the release of Sema3A in retinal ganglion cells-5, which in turn induced apoptosis of microvascular endothelium; antagonism of IL-1 receptor decreased microglial activation and on retinal ganglion cells-5 abolished the release of Sema3A inhibiting ensuing endothelial cell apoptosis. IL-1β was not directly cytotoxic to endothelial cells.
  
  
  CONCLUSIONS
  Our findings suggest that in the early stages of O2-induced retinopathy, retinal microglia are activated to produce IL-1β, which sustains the activation of microglia and induces microvascular injury through the release of Sema3A from adjacent neurons. Interference with IL-1 receptor or Sema3A actions preserves the microvascular bed in ischemic retinopathies and, consequently, decreases ensued pathological preretinal neovascularization.
authors.affiliation: Department of Pediatrics, Ophthalmology, and Pharmacology, CHU Sainte-Justine Research Center, Paris, France.
authors.forename: José Carlos
authors.initials: JC
authors.lastname: Rivera
authors.forename: Nicholas
authors.initials: N
authors.lastname: Sitaras
authors.forename: Baraa
authors.initials: B
authors.lastname: Noueihed
authors.forename: David
authors.initials: D
authors.lastname: Hamel
authors.forename: Ankush
authors.initials: A
authors.lastname: Madaan
authors.forename: Tianwei
authors.initials: T
authors.lastname: Zhou
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Honoré
authors.forename: Christiane
authors.initials: C
authors.lastname: Quiniou
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Joyal
authors.forename: Pierre
authors.initials: P
authors.lastname: Hardy
authors.forename: Florian
authors.initials: F
authors.lastname: Sennlaub
authors.forename: William
authors.initials: W
authors.lastname: Lubell
authors.forename: Sylvain
authors.initials: S
authors.lastname: Chemtob
mesh_terms: D000818:Animals; D018501:Antirheumatic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D002352:Carrier Proteins; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D055785:Gene Knockdown Techniques; D018496:Hyperoxia / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D007511:Ischemia / Q000188:drug therapy / Q000276:immunology / Q000473:pathology*; D008833:Microcirculation / Q000502:physiology; D017628:Microglia / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D018384:Oxidative Stress / Q000187:drug effects / Q000276:immunology; D010455:Peptides / Q000494:pharmacology; D061251:Primary Cell Culture; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000276:immunology / Q000378:metabolism; D012164:Retinal Diseases / Q000188:drug therapy / Q000276:immunology / Q000473:pathology*; D012165:Retinal Ganglion Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D012173:Retinitis / Q000188:drug therapy / Q000276:immunology / Q000473:pathology*; D040121:Semaphorin-3A / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: C529594:101.10 peptide; D018501:Antirheumatic Agents; D002352:Carrier Proteins; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C573346:Nlrp3 protein, rat; D010455:Peptides; D018160:Receptors, Cytoplasmic and Nuclear; C488218:Sema3a protein, rat; D040121:Semaphorin-3A
keywords: diabetic retinopathy; interleukin-1β; microglia; retinopathy of prematurity; semaphorin-3A; vaso-obliteration