title: Complement deposition and microglial activation in the outer retina in light-induced retinopathy: inhibition by a 5-HT1A agonist.
abstract: OBJECTIVE
  Increasing evidence supports a role for complement in the pathogenesis of age-related macular degeneration (AMD). This study evaluated retinal microglia, T-lymphocytes, and complement deposition in a light-induced retinopathy model. The effect of a serotonin (5-hydroxytryptamine, 5-HT(1A)) agonist on these processes was investigated.
  
  
  METHODS
  Rats were dark adapted for 24 hours before a 6-hour blue light exposure. Some animals were predosed subcutaneously with AL-8309A. Retinas were evaluated at different times after light exposure. Paraffin sections were stained with antibody for a microglial marker (Iba1), a T-lymphocyte marker (CD3), and complement components C1q, C3, factor B, factor H, and membrane attack complex (MAC).
  
  
  RESULTS
  Light exposure resulted in substantial photoreceptor and RPE loss. Robust microglia activation and migration to the outer retina occurred rapidly. Substantial T-lymphocyte recruitment did not occur. Complement alternative pathway was strongly activated, resulting in the deposition of C3, factor B, factor H, and MAC in the area of photic lesions. Dosing with AL-8309A prevented retinal lesions and decreased microglia activation/recruitment and complement deposition in the outer retina.
  
  
  CONCLUSIONS
  In blue light exposed retinas, microglia were activated and migrated toward the outer retina, whereas a T-lymphocyte response was minimal. The innate immune system was markedly activated, with substantial complement deposition in the outer retina after light exposure. This complement deposition was prevented by AL-8309A. This model may be useful in the evaluation of complement inhibitors and other neuroprotectants intended for ocular use. AL-8309 is under evaluation in the clinic and may be useful in the treatment of AMD.
authors.affiliation: Alcon Research, Ltd., Fort Worth, Texas 76134-2099, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Collier
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.forename: Sherry S
authors.initials: SS
authors.lastname: Smith
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Martin
authors.forename: Richard
authors.initials: R
authors.lastname: Ornberg
authors.forename: Kristina
authors.initials: K
authors.lastname: Rhoades
authors.forename: Carmelo
authors.initials: C
authors.lastname: Romano
mesh_terms: D000818:Animals; D002452:Cell Count; D002465:Cell Movement; D003176:Complement C3 / Q000378:metabolism; D011415:Complement Factor B / Q000378:metabolism; D017242:Complement Factor H / Q000378:metabolism; D015938:Complement Membrane Attack Complex / Q000378:metabolism; D003165:Complement System Proteins / Q000378:metabolism*; D003623:Dark Adaptation; D007150:Immunohistochemistry; D007279:Injections, Subcutaneous; D008027:Light / Q000009:adverse effects*; D017628:Microglia / Q000378:metabolism*; D018384:Oxidative Stress / Q000528:radiation effects; D011833:Radiation Injuries, Experimental / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000528:radiation effects*; D012162:Retinal Degeneration / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D058825:Serotonin 5-HT1 Receptor Agonists / Q000627:therapeutic use*; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D003176:Complement C3; D015938:Complement Membrane Attack Complex; D058825:Serotonin 5-HT1 Receptor Agonists; D017242:Complement Factor H; D003165:Complement System Proteins; D011415:Complement Factor B