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New Insights on Complement Inhibitor CD59 in Mouse Laser-Induced Choroidal Neovascularization: Mislocalization After Injury and Targeted Delivery for Protein Replacement.

PURPOSE
The membrane attack complex (MAC) in choriocapillaris (CC) and retinal pigment epithelium (RPE) increase with age and disease (age-related macular degeneration). MAC assembly can be inhibited by CD59, a membrane-bound regulator. Here we further investigated the role of CD59 in murine choroidal neovascularization (CNV), a model involving both CC and RPE, and tested whether CR2-CD59, a soluble targeted form of CD59, provides protection.


METHODS
Laser-induced CNV was generated in wild type and CD59a-deficient mice (CD59-/-). CNV size was measured by optical coherence tomography, and CR2-CD59 was injected intraperitoneally. Endogenous CD59 localization and MAC deposition were identified by immunohistochemistry and quantified by confocal microscopy. Cell-type-specific responses to MAC were examined in retinal pigment epithelial cells (ARPE-19) and microvascular endothelial cells (HMEC-1).


RESULTS
CD59 levels were severely reduced and protein was mislocalized in the RPE surrounding the lesion. CNV lesion size and subretinal fluid accumulation were exacerbated in CD59-/- when compared with those in WT mice, and an increase in MAC deposition was noted. In contrast, CR2-CD59 significantly reduced both structural features of CNV severity. In vitro, MAC inhibition in ARPE-19 cells prevented barrier function loss and accelerated wound healing and cell adhesion, whereas in HMEC-1 cells, CR2-CD59 decelerated wound healing and cell adhesion.


CONCLUSION
These data further support the importance of CD59 in controlling ocular injury responses and indicate that pharmacological inhibition of the MAC with CR2-CD59 may be a viable therapeutic approach for reducing complement-mediated ocular pathology.