Differential analysis of core complement components expression and localization across rodent, non-human primate, and human ocular tissues

Abstract

Age-related macular degeneration (AMD) is a leading cause of blindness. Genetic and pathophysiological studies have implicated that complement pathway dysfunction is a key contributor to progressive vision loss in AMD. Though the association between complement and AMD is recognized, numerous anti-complement therapeutics that had been tested in rodent model systems had limited success in clinical trials. Understanding complement factor production and site of action in ocular pathophysiology is critical for the development of efficacious therapeutics. However, our limited understanding of how these aspects of complement biology vary across species restricts our ability to predict clinical outcomes from studies using animal models. Here, we integrated transcriptomic and immunohistochemical assays to understand the expression and localization of core complement components (complement factor H (FH), complement 3 (C3), and complement 5 (C5)) between ocular tissues of rodent, non-human primate, and human species. We found that complement distribution varied significantly across the studied species, with the most striking differences observed in the FH. While rodents expressed Cfh, an alternative pathway inhibitor, mainly in the RPE, CFH expression in primate eyes was primarily confined to the choroid. These differences were consistent at the protein level, with rodent FH localized in the RPE and primate FH within the choriocapillaris, choroid and sclera. Regarding C5, a terminal complement pathway component, we observed minimal ocular mRNA levels in all three species. However, we observed detectable protein levels in the RPE in rodents and the choroid in humans. Next, C3 mRNA transcripts and C3 protein exhibited similar distribution in the choroid in both rodent and primate eyes. Together, our findings highlight key differences and similarities between rodent and primate complement biology that may offer insights into the translatability of animal models and inform the design of effective therapeutics.