Oxidative damage-induced inflammation initiates age-related macular degeneration.
Oxidative damage and inflammation are postulated to be involved in age-related macular degeneration (AMD). However, the molecular signal(s) linking oxidation to inflammation in this late-onset disease is unknown. Here we describe AMD-like lesions in mice after immunization with mouse serum albumin adducted with carboxyethylpyrrole, a unique oxidation fragment of docosahexaenoic acid that has previously been found adducting proteins in drusen from AMD donor eye tissues and in plasma samples from individuals with AMD. Immunized mice develop antibodies to this hapten, fix complement component-3 in Bruch's membrane, accumulate drusen below the retinal pigment epithelium during aging, and develop lesions in the retinal pigment epithelium mimicking geographic atrophy, the blinding end-stage condition characteristic of the dry form of AMD. We hypothesize that these mice are sensitized to the generation of carboxyethylpyrrole adducts in the outer retina, where docosahexaenoic acid is abundant and conditions for oxidative damage are permissive. This new model provides a platform for dissecting the molecular pathology of oxidative damage in the outer retina and the immune response contributing to AMD.
Hollyfield
Joe G
JG
Cole Eye Institute (i31), Department of Ophthalmology, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio 44195, USA.
Bonilha
Vera L
VL
Rayborn
Mary E
ME
Yang
Xiaoping
X
Shadrach
Karen G
KG
Lu
Liang
L
Ufret
Rafael L
RL
Salomon
Robert G
RG
Perez
Victor L
VL
D000375:Aging; D000818:Animals; D000906:Antibodies / Q000276:immunology; D000941:Antigens / Q000276:immunology; D016570:Bruch Membrane / Q000473:pathology / Q000648:ultrastructure; D015933:Complement C3d / Q000378:metabolism; D007114:Immunization; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology*; D008268:Macular Degeneration / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D010857:Pigment Epithelium of Eye / Q000473:pathology / Q000648:ultrastructure; D021381:Protein Transport; D011758:Pyrroles / Q000378:metabolism; D013997:Time Factors; D017186:Titrimetry
D000906:Antibodies; D000941:Antigens; D011758:Pyrroles; D015933:Complement C3d