Cd59a deficiency in mice leads to preferential innate immune activation in the retinal pigment epithelium–choroid with age

• Published in: Neurobiology of aging Vol. 36; no. 9; pp. 2637 - 2648
• Main Authors: Herrmann, Philipp, Cowing, Jill A, Cristante, Enrico, Liyanage, Sidath E, Ribeiro, Joana, Duran, Yanai, Abelleira Hervas, Laura, Carvalho, Livia S, Bainbridge, James W.B, Luhmann, Ulrich F.O, Ali, Robin R
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2015
• Subjects: Age-related retinal degeneration; Aging; Aging - genetics; AMD; Analysis of Variance; Animals; CD59 Antigens - genetics; CD59 Antigens - metabolism; Cd59a; Choroid - metabolism; Choroid - pathology; Complement Activation; Complement dysregulation; Complement regulator; Disease Models, Animal; Electroretinography; Gene Expression Regulation - genetics; Immunologic Factors - metabolism; Internal Medicine; Macrophages - metabolism; Macrophages - pathology; Macular Degeneration - genetics; Macular Degeneration - metabolism; Macular Degeneration - pathology; Mice; Mice, Inbred C57BL; Mice, Knockout; Microglia - metabolism; Microglia - pathology; Nerve Tissue Proteins - genetics; Neurology; Retina - pathology; Retinal Pigment Epithelium - metabolism; Retinal Pigment Epithelium - pathology; RNA, Messenger - metabolism; AMD; Aging; Cd59a; Complement dysregulation; Complement regulator; Age-related retinal degeneration
• ISSN: 0197-4580; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2015.05.019

Abstract Dysregulation of the complement system has been implicated in the pathogenesis of age-related macular degeneration. To investigate consequences of altered complement regulation in the eye with age, we examined Cd59a complement regulator deficient ( Cd59a −/− ) mice between 4 and 15 months. In vivo imaging revealed an increased age-related accumulation of autofluorescent spots in Cd59a −/− mice, a feature that reflects accumulation of subretinal macrophages and/or microglia. Despite this activation of myeloid cells in the eye, Cd59a −/− mice showed normal retinal histology and function as well as normal choroidal microvasculature. With age, they revealed increased expression of activators of the alternative complement pathway ( C3 , Cfb, Cfd ), in particular in the retinal pigment epithelium (RPE)-choroid but less in the retina. This molecular response was not altered by moderately-enhanced light exposure. Cd59a deficiency therefore leads to a preferential age-related dysregulation of the complement system in the RPE-choroid, that alone or in combination with light as a trigger, is not sufficient to cause choroidal vascular changes or retinal degeneration and dysfunction. This data emphasizes the particular vulnerability of the RPE-choroidal complex to dysregulation of the alternative complement pathway during aging.