Complement activation by photooxidation products of A2E, a lipofuscin constituent of the retinal pigment epithelium.
Recent studies have implicated local inflammation and activation of complement amongst the processes involved in the pathogenesis of age-related macular degeneration (AMD). Several lines of investigation also indicate that bis-retinoid pigments, such as A2E, that accumulate as lipofuscin in retinal pigment epithelial (RPE) cells, contribute to the disease process. In an investigation of a potential trigger for complement activation in AMD, we explored the notion that the complex mixture of products resulting from photooxidation of A2E might include a range of fragments that could be recognized by the complement system as "foreign" and that could serve to activate the complement system, leading to low-grade inflammation. To this end, we established an in vitro assay by using human serum as a source of complement, and we measured products of C3 activation by enzyme immunoassay. Accordingly, we found that the C3 split products inactivated C3b (iC3b) and C3a were elevated in serum, overlying ARPE-19 cells that had accumulated A2E and were irradiated to induce A2E photooxidation. Precoating of microtiter plates with two species of oxidized A2E, peroxy-A2E, and furano-A2E, followed by incubation with serum, also activated complement. We suggest that products of the photooxidation of bis-retinoid lipofuscin pigments in RPE cells could serve as a trigger for the complement system, a trigger than would predispose the macula to disease and that, over time, could contribute to chronic inflammation. These findings link four factors that have been posited as being associated with AMD: inflammation, oxidative damage, drusen, and RPE lipofuscin.
Zhou
Jilin
J
Department of Ophthalmology, Columbia University, New York, NY 10032, USA.
Jang
Young Pyo
YP
Kim
So Ra
SR
Sparrow
Janet R
JR
D002460:Cell Line; D015926:Complement C3a / Q000096:biosynthesis*; D003179:Complement C3b / Q000096:biosynthesis* / Q000737:chemistry; D004848:Epithelium / Q000737:chemistry / Q000378:metabolism; D005663:Furans / Q000378:metabolism; D006801:Humans; D008062:Lipofuscin / Q000737:chemistry / Q000378:metabolism*; D013058:Mass Spectrometry; D015394:Molecular Structure; D010084:Oxidation-Reduction; D010777:Photochemistry; D011726:Pyridinium Compounds / Q000737:chemistry / Q000378:metabolism*; D012168:Retinal Pigments / Q000737:chemistry / Q000378:metabolism*; D012176:Retinoids / Q000737:chemistry / Q000378:metabolism*
C112040:A2-E (N-retinylidene-N-retinylethanolamine); D005663:Furans; D008062:Lipofuscin; D011726:Pyridinium Compounds; D012168:Retinal Pigments; D012176:Retinoids; D015926:Complement C3a; D003179:Complement C3b; C039281:furan