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Published on: March 30, 2020
Complement regulatory protein CD46 protects against choroidal neovascularization in mice
Valeriy Lyzogubov1, Xiaobo Wu2, Purushottam Jha1
1Department of Ophthalmology, Pat and Willard Walker Eye Research Center, Jones Eye Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
Insights
The complement regulator CD46 is present in the mouse eye and protects against choroidal neovascularization (CNV). CD46 deficiency increases susceptibility to experimental CNV due to complement dysregulation.
Area of Science:
- Ophthalmology
- Immunology
- Complement System Biology
Background:
- Complement system dysregulation is implicated in age-related macular degeneration.
- CD46, a complement regulator, is ubiquitously expressed in humans but was thought to be restricted to spermatozoa in mice.
- The role of CD46 in ocular tissues and its impact on neovascularization remain unclear.
Purpose of the Study:
- To investigate CD46 expression in the mouse eye.
- To determine the role of CD46 in experimental choroidal neovascularization (CNV).
- To explore the link between CD46, complement activation, and VEGF in the context of CNV.
Main Methods:
- Detection of CD46 mRNA and protein in posterior ocular segments of wild-type (WT) C57BL/6J mice.
- Analysis of membrane attack complex (MAC) and vascular endothelial growth factor (VEGF) levels in Cd46(-/-) knockout mice.
- Assessment of susceptibility to laser-induced CNV in WT and Cd46(-/-) mice, quantifying positive spots and lesion size over time.
Main Results:
- CD46 mRNA and protein were detected in the retina, retinal pigment epithelium, and choroid of WT mice.
- Cd46(-/-) mice showed elevated MAC and VEGF levels in the retina and choroid.
- Cd46(-/-) mice exhibited significantly increased susceptibility to laser-induced CNV, with higher incidence and larger lesion sizes compared to WT mice.
Conclusions:
- CD46 is expressed in the posterior segment of the mouse eye.
- CD46 plays a protective role against laser-induced choroidal neovascularization.
- CD46 deficiency exacerbates experimental CNV, likely due to impaired complement inhibition leading to increased MAC deposition and VEGF expression.
Abstract:
Dysregulation of the complement system is increasingly recognized as a contributing factor in age-related macular degeneration. Although the complement regulator CD46 is expressed ubiquitously in humans, in mouse it was previously thought to be expressed only on spermatozoa. We detected CD46 mRNA and protein in the posterior ocular segment (neuronal retina, retinal pigment epithelium, and choroid) of wild-type (WT) C57BL/6J mice. Cd46(-/-) knockout mice exhibited increased levels of the membrane attack complex and of vascular endothelial growth factor (VEGF) in the retina and choroid. The Cd46(-/-) mice were also more susceptible to laser-induced choroidal neovascularization (CNV). In Cd46(-/-) mice, 19% of laser spots were positive for CNV at day 2 after treatment, but no positive spots were detected in WT mice. At day 3, 42% of laser spots were positive in Cd46(-/-) mice, but only 11% in WT mice. A fully developed CNV complex was noted in both Cd46(-/-) and WT mice at day 7; however, lesion size was significantly (P < 0.05) increased in Cd46(-/-) mice. Our findings provide evidence for expression of CD46 in the mouse eye and a role for CD46 in protection against laser-induced CNV. We propose that the Cd46(-/-) mouse has a greater susceptibility to experimental CNV because of insufficient complement inhibition, which leads to increased membrane attack complex deposition and VEGF expression.
