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Sha-Mei Liao, Natasha Buchanan, John Demirs, Barrett Leehy, Casey Lewis, Junzheng Yang, Vanessa Davis, Nalini V Rangaswamy, Maura Crowley, Karen Anderson, Chad E Bigelow, Thaddeus P Dryja, Bruce D Jaffee; Deletion of complement factor H is associated with accumulation of subretinal Iba-1-positive cells and retinal degeneration in aged mice. Invest. Ophthalmol. Vis. Sci. 2017;58(8):1625.
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Despite the contrasting roles that complement factor H (Cfh) and complement factor P (Cfp) play in alternative pathway regulation, it has been reported that deletion of Cfp in the Cfh-deficient mouse model of dense deposit disease results in exacerbation, rather than moderation, of the glomerulopathy. In order to investigate the role of Cfh and Cfp in complement-mediated eye pathology, Cfh and Cfp single and double knock-out mice were evaluated.
Male and female Cfh and Cfp single and double knock-out mice were aged from 2 to 9 months. Animals were assessed by fundus photography, optical coherence tomography (OCT), and scanning laser ophthalmoscopy (SLO). Ocular flatmounts and tissue sections were examined for F4/80- and Iba-1-positive cells. Kidney sections were immunostained for complement and Iba-1. Urine was collected to measure albuminuria as an indicator of renal function. Kidney samples were assessed for cytokine production by multiplex cytokine analysis. The two-tailed unpaired t-test was used for statistical analyses.
Cfh-/-Cfp+/+ and Cfh-/-Cfp-/- mice exhibited retinal flecks by funduscopy (15/19 and 16/21 mice, respectively) and SLO imaging (7/7 and 8/8 mice, respectively). OCT revealed retinal thinning in a subset of these animals (Cfh-/-Cfp+/+, 3/8 mice; Cfh-/-Cfp-/-, 3/8 mice) that was confirmed histologically, and subretinal Iba-1-positive cells were identified in both Cfh-/-Cfp+/+ mice (4/4) and Cfh-/-Cfp-/- mice (4/4). No eye abnormalities were observed in either littermate control Cfh+/+Cfp+/+ mice or Cfh+/+Cfp-/- mice. An increase in inflammatory proteins (IL-1β, p<0.01 and TNFα, p<0.01) and complement deposition (p<0.05) was observed in the kidneys of Cfh-/-Cfp+/+ animals. Cfh-/-Cfp-/- mice exhibited an additional increase in inflammatory proteins (IL-1β, p<0.001, and TNFα, p<0.05), complement deposition (p<0.01) in the kidneys, and microalbuminuria, as compared to the Cfh-/-Cfp+/+ mice (p<0.01).
Aged Cfh-/-Cfp+/+ and Cfh-/-Cfp-/- mice exhibited retinal abnormalities, specifically retinal flecks, atrophy, retinal thinning and accumulation of subretinal Iba-1-positive cells. The ocular pathology was not observed in Cfh+/+Cfp-/- mice. Our results provide evidence that chronic over-activation of complement due to a deficiency in complement factor H recapitulates characteristic features of AMD.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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