Inflammazone Driven Chronic Inflammation in the Progression of Age-Related Macular Degeneration
The later, "wet" stages of macular degeneration involve the inappropriate formation of leaky blood vessels under the retina, destroying its integrity and function. This is in large part driven by chronic inflammation and the altered cell behavior that it causes. Researchers here focus on one specific class of regulators of inflammation and its role in the progression of macular degeneration.
Inflammasomes are multiprotein complexes that lead to the proteolytic activation of proinflammatory IL-1β and IL-18 through the catalytic activity of caspase-1. Canonical inflammasome activation is initiated by cytosolic pattern recognition receptors (PRRs) when exposed to specific triggers, either microbe-derived pathogen-associated molecular patterns (PAMPs) or host-derived danger-associated molecular patterns (DAMPs). These PRRs include the family of NOD-like receptors, to which NLRP3 belongs.
Recent studies implicated canonical inflammasome activation in age-related macular degeneration (AMD) pathogenesis. However, these studies have focused on the NLRP3 inflammasome and did not consider a potential contribution of other PRRs for inflammasome activation in AMD. 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. This has led to the assumption that AMD risk factors promote NLRP3 inflammasome activation, which further exacerbates AMD pathologies through activation of proinflammatory cytokines, such as IL-1β that is known to stimulate inflammatory angiogenesis.
Key open questions are (1) whether NLRP3 inflammasome activation mainly in retinal pigment epithelium (RPE) or rather in non-RPE cells promotes choroidal neovascularization (CNV), (2) whether inflammasome activation in CNV occurs via NLRP3 or also through NLRP3-independent mechanisms, and (3) whether complement activation induces inflammasome activation in CNV.
Here we show in a neovascular AMD mouse model that NLRP3 inflammasome activation in non-RPE cells but not in RPE cells promotes CNV. We demonstrate that both NLRP3-dependent and NLRP3-independent inflammasome activation mechanisms induce CNV. Finally, we find that complement and inflammasomes promote CNV through independent mechanisms. Our findings uncover an unexpected role of non-NLRP3 inflammasomes for CNV and suggest that combination therapies targeting inflammasomes and complement may offer synergistic benefits to inhibit CNV.