New research reveals insights into potential drivers of the disease, which currently has no cure, that could be addressed through prevention or treatment strategies. Findings from the study by researchers at Massachusetts General Hospital (MGH) are published in eLife.
Two inflammatory pathways involving complement (which is a component of the immune system) and a protein complex called an inflammasome (which, as the name suggests, triggers inflammation) promote the formation of abnormal blood vessels that are characteristic of wet AMD, but it is unclear how these pathways are activated. Previous studies suggest that the inflammasome may be activated by a protein called NLRP3, primarily in the retinal pigment epithelium of the eye (a cell layer that separates the vascular layer of the eye from the retina).
To investigate further, the researchers conducted experiments on a wet AMD mouse model. The team showed that inflammation of the inflammasome by NLRP3 occurs mainly in cells called macrophages and microglia, but not in the retinal pigment epithelium. The scientists also found that proteins other than NLRP3 can lead to inflammation of the inflammasome and worsening of wet AMD. “This means that instead of targeting only NLRP3 in wet AMD, it may be beneficial to block essential inflammasome proteins that are necessary for its activation, regardless of whether NLRP3 or other proteins initiate inflammation of the inflammasome,” says lead author. Alexander G. Marneros, MD, PhD, principal investigator at MGH’s Cutaneous Biology Research Center and associate professor of dermatology at Harvard Medical School. “Our findings provide guidance on how to block inflammasomes in wet AMD.”
Marneros notes that previous studies in cells suggest that complement activation may, in turn, lead to inflammation of the inflammasome, but this study in mice found that this activation occurs largely independently of 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 to the manifestation of AMD. wet, “he says. .
In addition to providing new insights into how inflammation is regulated in wet AMD, the study also suggests that new therapies that block inflammasome-mediated inflammation could be improved when combined with treatments that inhibit complement-mediated inflammation. “A combined therapeutic approach that blocks both inflammatory pathways will likely have synergistic effects in decreasing the symptoms of wet AMD. Therefore, our findings in this mouse model may have important clinical relevance for novel therapies for this common blindness disease. “says Marneros. (AND ME)
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