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SW Cousins, KG Csaky; Macrophage Function in Age-Related Macular Degeneration (AMD) . Invest. Ophthalmol. Vis. Sci. 2002;43(13):864.
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Purpose: Innate immunity, especially macrophage recruitment to the choroid by cytokines or deposits produced by the RPE, has been proposed to contribute to AMD pathogenesis. Macrophages have been observed to insert membrane processes into drusen and to infiltrate within choroidal neovascularization (CNV). We evaluated macrophage function from patients with AMD and in mouse models for subRPE deposit formation or experimental CNV. Methods: Circulating monocytes were obtained from the blood of subjects with AMD or age-matched controls by gradient centrifugation, then analyzed for either TNF-α mRNA content by RT-PCR or for analysis of TNF-α release of cultured macrophages in response to RPE-derived blebs and cytokines. In a mouse model for laser-induced CNV, macrophage infiltration was assessed by histochemistry. Functional contribution was evaluated by systemic activation with endotoxin or depletion by clodronate. Results: In human monocytes obtained from control and AMD subjects, TNF-α was expressed by freshly isolated monocytes and was produced by macrophages in culture after stimulation with RPE derived blebs. However, wide variability in TNF-α expression was observed among different subjects, suggesting a subset of patients were either high or low responders. High-responders were especially prevalent in patients with CNV. In the mouse model of CNV, macrophages were numerous in the early phases of CNV formation, and macrophage depletion significantly diminished CNV size and severity. Conclusion: Different subsets of macrophage responsiveness may exist among individuals: a "low-responsive" subset in which macrophages scavenge RPE debris without activation and a "high-responsive" subset in which macrophages inappropriately become stimulated by RPE blebs or debris. Patients with "high-responsive" macrophages may be at risk for CNV formation.
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