Infiltration of Proinflammatory M1 Macrophages into the Outer Retina Precedes Damage in a Mouse Model of Age-Related Macular Degeneration

Abstract

Age-related macular degeneration (AMD) is a major cause of blindness in the developed world. Oxidative stress and inflammation are implicated in AMD, but precise mechanisms remain poorly defined. Carboxyethylpyrrole (CEP) is an AMD-associated lipid peroxidation product. We previously demonstrated that mice immunized with CEP-modified albumin developed AMD-like degenerative changes in the outer retina. Here, we examined the kinetics of lesion development in immunized mice and the presence of macrophages within the interphotoreceptor matrix (IPM), between the retinal pigment epithelium and photoreceptor outer segments. We observed a significant and time-dependent increase in the number of macrophages in immunized mice relative to young age-matched controls prior to overt pathology. These changes were more pronounced in BALB/c mice than in C57BL/6 mice. Importantly, IPM-infiltrating macrophages were polarized toward the M1 phenotype but only in immunized mice. Moreover, when Ccr2-deficient mice were immunized, macrophages were not present in the IPM and no retinal lesions were observed, suggesting a deleterious role for these cells in our model. This work provides mechanistic evidence linking immune responses against oxidative damage with the presence of proinflammatory macrophages at sites of future AMD and experimentally demonstrates that manipulating immunity may be a target for modulating the development of AMD.

Increased Th1/Th17 Responses Contribute to Low-Grade Inflammation in Age-Related Macular Degeneration

“…In our study, we defined Th1 and Th17 cells functionally by the expression of characteristic cytokines, and found that the frequencies of IFN-γ-and IL-17-expressing CD4 + T cells, as well as the levels of IFN-γ and IL-17 expression by CD4 + T cells, were significantly upregulated in AMD patients. Hence, the discrepancy in our conclusions likely arose from the different definitions being used to Given that M1 macrophages were previously linked with the development of retinal lesions in mouse model [20], Th1 cell and Th17 cells might function to accelerate the development of AMD and exacerbate the symptoms. Further research in animal models is necessary to establish a causal link.…”

“…Many studies in animal models have established causal links between retinal damage and proinflammatory pathways [20][21][22]. In humans, many studies have shown that AMD patients presented higher expression of proinflammatory cytokines and altered phenotype and functions of immune cells [16,23,24].…”

“…[19]. Prior to the induction of retinal lesion, macrophages enriched in the M1 type were found to infiltrate the interphotoreceptor matrix in mice, while in CCR2-deficient mice with no infiltration of macrophages, no retinal lesion was observed [20]. Macrophages also stimulate the expression of complement factors and other inflammatory mediators by RPE cells through soluble macrophage-derived cytokines [21].…”

Genomic aspects of age-related macular degeneration

“…Although the specific 184 roles of macrophages at different disease stages remain controver- 185 sial, both pro-inflammatory M1 macrophages and anti-inflamma- 186 tory M2 macrophages may be involved in the development and 187 progression of AMD. Recent studies have revealed that macro- 188 phages recruited under the retina at the initial stage of AMD exhi- 189 bit a pro-inflammatory M1 phenotype [32][33][34]. T cells may also be 190 involved in the pathology, as shown by a study of carboxyethylpyr- 191 role-immunized mice, which exhibit AMD-like pathology [33].…”

Association Between Aqueous Humor CXC Motif Chemokine Ligand 13 Levels and Subfoveal Choroidal Thickness in Normal Older Subjects

“…37,38 Thus, it remains to be unknown whether CXCL13 plays causative role for thickened choroid. Alternatively, as choroidal vessels are dilated in the thickened choroid, another possible explanation of the higher concentration of CXCL13 in the aqueous humor may be due to the higher production of CXCL13 that is attributable to the increased vascularity of the choroid.…”