Abstract
Purpose :
Inflammation is known to play a role in the pathogenesis of age-related macular degeneration (AMD). Our previous research has shown increased expression of interferon-γ (IFN-γ) inducible chemokines including IP-10 (CXCL-10) and MIG (CXCL-9) in sera and ocular samples of subjects with AMD. The levels of these proinflammatory chemokines increase with the disease stage. Herein, we investigated whether circulating monocytes and tissue macrophages were the sources of chemokine expression in AMD.
Methods :
Matched postmortem ocular and spleen specimens, staged for AMD, and non-AMD controls were subjected to immunohistochemistry (IHC) for expression of chemokines IP-10, MIG, I-TAC and CXCR3, as well as co-labeled for expression of monocyte/macrophage markers, CD163 and CD68. Whole blood samples were collected from subjects with various stages of AMD (AREDS classification) and age-matched controls and subjected to flow cytometry analysis (FACS) for co-expression of these chemokines with leukocyte markers, including CD14 (monocyte), CD3 (T-cell) and CD20 (B-cell).
Results :
IHC of eyes with AMD showed expression of these chemokines in RGC/nerve fiber layer, outer retina, drusen deposit and RPE, and increased with the stage of AMD. In spleens, increased expression of IP-10 was observed in both early and intermediate dry AMD compared to non-AMD controls (30% and 28%, respectively, vs. 18%; P<0.05 each). Interestingly, MIG expression was significantly decreased in early and intermediate AMD compared to controls (0.6% and 1.4%, respectively, vs. 5.2%; P<0.01 each). IHC also showed co-expression of CD68 and CD163 in these cells, suggesting a monocyte/macrophage source for these chemokines. FACS analysis of AMD blood showed increased expression of IP-10 and MIG (P<0.05 each) in circulating CD14+ cells, confirming that systemic monocytes participate in AMD.
Conclusions :
Combined data and observations of postmortem specimens indicate that IFN-γ inducible chemokines participate in AMD both at the local and systemic levels. Monocytes/macrophages expressing CD14, CD163 and CD68 are the most likely sources of chemokine production in AMD and maintain a proinflammatory state. These chemokines and their receptor may be novel therapeutic targets for treatment of dry AMD.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.