Distinct effects of complement and of NLRP3- and non-NLRP3 inflammasomes for choroidal neovascularization.

NLRP3 inflammasome activation and complement-mediated inflammation have been implicated in promoting choroidal neovascularization (CNV) in age-related macular degeneration (AMD), but central questions regarding their contributions to AMD pathogenesis remain unanswered. Key open questions are (1) whether NLRP3 inflammasome activation mainly in retinal pigment epithelium (RPE) or rather in non-RPE cells promotes 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.

NLRP3炎症小体激活和补体介导的炎症与年龄相关性黄斑变性（AMD）中脉络膜新生血管形成（CNV）的促进有关，但关于它们对AMD发病机制的贡献的核心问题仍未得到解答。关键的未解决问题是：（1）NLRP3炎症小体激活主要是在视网膜色素上皮（RPE）中还是在非RPE细胞中促进CNV；（2）CNV中的炎症小体激活是通过NLRP3还是也通过不依赖NLRP3的机制发生；（3）补体激活是否在CNV中诱导炎症小体激活。在此，我们在一种新生血管性AMD小鼠模型中表明，非RPE细胞中的NLRP3炎症小体激活而非RPE细胞中的激活促进CNV。我们证明NLRP3依赖和NLRP3非依赖的炎症小体激活机制都会诱导CNV。最后，我们发现补体和炎症小体通过独立的机制促进CNV。我们的研究结果揭示了非NLRP3炎症小体在CNV中的意外作用，并表明针对炎症小体和补体的联合疗法可能为抑制CNV提供协同益处。