A new way to view wet AMD

New insights into age-related macular degeneration could lead to better treatments

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BOSTON—New research by investigators at Massachusetts General Hospital (MGH) has revealed information about potential drivers of wet age-related macular degeneration (AMD) that could be targeted through prevention or treatment strategies. The findings have been published in eLife.

Two inflammatory pathways involving complement — an immune system component — and the inflammasome promote the formation of abnormal blood vessels that are hallmarks of wet AMD, but it’s been unclear how these pathways are activated. Previous studies have suggested that the inflammasome could be activated by a protein called NLRP3, found mainly in the retinal pigment epithelium of the eye.

Researchers conducted experiments in a mouse model of wet AMD, and showed that inflammasome activation by NLRP3 occurs primarily in cells called macrophages and microglia, but not in the retinal pigment epithelium. The scientists also discovered that other proteins besides NLRP3 can lead to inflammasome activation and worsening of wet AMD.

“This means that rather than targeting only NLRP3 in wet AMD, it may be beneficial to block essential proteins of the inflammasome instead that are required for its activation, independently of whether NLRP3 or other proteins initiate inflammasome activation,” noted senior author Alexander G. Marneros, M.D., Ph.D., a principal investigator at MGH’s Cutaneous Biology Research Center and an associate professor of Dermatology at Harvard Medical School. “Our findings provide guidance on how to block inflammasomes in wet AMD.”

“Recent studies implicated canonical inflammasome activation in AMD pathogenesis. However, these studies have focused on the NLRP3 inflammasome and did not consider a potential contribution of other PRRs [pattern recognition receptors] for inflammasome activation in AMD,” states the article. “The reason for this very narrow focus on NLRP3 as a PRR that initiates inflammasome activation in AMD is that various stimuli that are well-established risk factors for AMD, including increased oxidative stress or lipid accumulations, are known activators of the NLRP3 inflammasome (Guo et al., 2015; Latz et al., 2013; Schroder and Tschopp, 2010).”

“Notably, the size of CNV [choroidal neovascularization] lesions can be accurately quantified in this AMD mouse model by immunolabeling of choroidal flat mounts with the endothelial cell marker CD31 that strongly labels neovessels that protrude into the sub-RPE [retinal pigment epithelium] space (Figure 1A–E),” the article continues. “These neovessels affect the overlying RPE morphology, which can be visualized by labeling with phalloidin or immunolabeling for active β-catenin, both outlining RPE cell membranes (Figure 1A, B, D and E).” 

Marneros pointed out that previous studies conducted in cells suggest that complement activation can in turn lead to inflammasome activation — but this current study in mice has found that the activation occurs largely independently from complement-mediated inflammation. 

“Our study in a mouse model defines the cell types that contribute to inflammasome-mediated inflammation in wet AMD and uncovers the specific roles and contributions of NLRP3 inflammasomes, non-NLRP3-inflammasomes, and complement for the manifestation of wet AMD,” he said.

The study also suggests that novel therapies for blocking inflammasome-mediated inflammation could be improved, if they are combined with treatments that inhibit complement-mediated inflammation. 

“Collectively, our data demonstrate that VEGF-A-induced neovascular AMD-like pathologies are promoted through inflammasome activation that occurs predominantly in non-RPE cells, and which is only in part mediated by NLRP3 but can also occur independently of NLRP3, caspase-11, or complement C3 (Figure 6). Thus, therapeutic strategies that combine approaches to inhibit both inflammasome activation and complement-mediated inflammation could result in more potent inhibition of neovascular AMD than either treatment approach alone,” the article concludes.

“A combined therapeutic approach that blocks both these inflammatory pathways is likely going to have synergistic effects in lessening the symptoms of wet AMD,” added Marneros. “Thus, our findings in this mouse model may have important clinical relevance for novel therapies for this common blinding disease.”

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