Synthesis and propagation of complement C3 by microglia/monocytes in the aging retina.
BACKGROUND
Complement activation is thought to contribute to the pathogenesis of age-related macular degeneration (AMD), which may be mediated in part by para-inflammatory processes. We aimed to investigate the expression and localization of C3, a crucial component of the complement system, in the retina during the course of aging.


METHODS
SD rats were born and reared in low-light conditions, and euthanized at post-natal (P) days 100, 450, or 750. Expression of C3, IBA1, and Ccl- and Cxcl- chemokines was assessed by qPCR, and in situ hybridization. Thickness of the ONL was assessed in retinal sections as a measure of photoreceptor loss, and counts were made of C3-expressing monocytes.


RESULTS
C3 expression increased significantly at P750, and correlated with thinning of the ONL, at P750, and up-regulation of GFAP. In situ hybridization showed that C3 was expressed by microglia/monocytes, mainly from within the retinal vasculature, and occasionally the ONL. The number of C3-expressing microglia increased significantly by P750, and coincided spatiotemporally with thinning of the ONL, and up-regulation of Ccl- and Cxcl- chemokines.


CONCLUSIONS
Our data suggest that recruited microglia/monocytes contribute to activation of complement in the aging retina, through local expression of C3 mRNA. C3 expression coincides with age-related thinning of the ONL at P750, although it is unclear whether the C3-expressing monocytes are a cause or consequence. These findings provide evidence of activation of complement during natural aging, and may have relevance to cellular events underling the pathogenesis of age-related retinal diseases.
The John Curtin School of Medical Research, The Australian National University (ANU), Canberra, Australian Capital Territory, Australia.
Matt
M
Rutar
The John Curtin School of Medical Research, The Australian National University (ANU), Canberra, Australian Capital Territory, Australia; ANU Medical School, The Australian National University (ANU), Canberra, Australian Capital Territory, Australia.
Krisztina
K
Valter
The John Curtin School of Medical Research, The Australian National University (ANU), Canberra, Australian Capital Territory, Australia; ANU Medical School, The Australian National University (ANU), Canberra, Australian Capital Territory, Australia.
Riccardo
R
Natoli
The John Curtin School of Medical Research, The Australian National University (ANU), Canberra, Australian Capital Territory, Australia; ANU Medical School, The Australian National University (ANU), Canberra, Australian Capital Territory, Australia.
Jan M
JM
Provis
D000375:Aging / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D003176:Complement C3 / Q000235:genetics* / Q000378:metabolism*; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D017628:Microglia / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000166:cytology / Q000502:physiology*
D018925:Chemokines; D003176:Complement C3; D005904:Glial Fibrillary Acidic Protein