Identifying the Roles of Interferon-Gamma Inducible Chemokines in Progression of Age-related Macular Degeneration (AMD)

Abstract

 

Purpose:

 

Local and possibly systemic inflammation play important roles in AMD; understanding the profile and activity of pro-inflammatory factors may elucidate the underlying mechanisms that participate in AMD and identify individuals at increased risk. We have previously identified interferon inducible factor-10 (IP-10) as one of the pro-inflammatory chemokines in the sera of subjects with AMD. In this study we have investigated the potential systemic cellular sources of interferon-inducible chemokines (CXC) and their receptor, CXCR3. Other CXC chemokines include monokine induced by interferon-gamma (MIG/CXCL9) and interferon-inducible T-cell alpha chemoattractant (I-TAC/CXCL11).

 

Methods:

 

Subjects with AMD were clinically classified as one of the following phenotypes, AREDS stages 1 and 3, geographic atrophy, active and inactive neovascular AMD. Buffy coats were derived from whole blood samples and subjected to flow cytometry analysis for expression of MIG, IP-10, I-TAC and CXCR3 in the circulating leukocytes. Matched postmortem eye and spleen samples were collected. Expression of these chemokines was examined by immunohistochemistry (IHC).

 

Results:

 

Flow cytometry showed elevated levels of MIG, IP-10 and I-TAC in patients of all AMD phenotypes as compared to controls. This shows that certain circulating leukocytes express the CXC chemokine system and probably contribute to their elevated serum levels. IHC of matched spleens of AMD donors showed that CXC expression was elevated in spleen cells as early as early stage AMD. Similarly, in postmortem eyes with early AMD, CXC expression was increased in the RPE and subsequently in basal linear/laminar deposits in all other stages of AMD.

 

Conclusions:

 

Studies indicate that CXC chemokines are elevated in subjects with AMD and may contribute as a systemic source to maintain a pro-inflammatory state in subjects with AMD. CXC chemokines are also upregulated in RPE cells in eyes with AMD. These chemokines and their receptor may be novel therapeutic targets for anti-inflammatory treatment of AMD.

 

Keywords: age-related macular degeneration • inflammation • cytokines/chemokines