Innate Immunity and NLRP3 inflammasome activation in pathologic neovascularization

摘要 病理性新生血管是炎症过程中的一个重要方面。NLRP3 炎性小体激活被认为是病理性血管生成的主要调节因素。 通过分泌促血管生成因子(如IL-1、β)。靶向NLRP3炎症体 或者它的调节剂可能因此代表了一种抑制炎症的新的治疗方法 和病理性新生血管。例如，我们可以在一只新的遗传小鼠中展示 血管内皮生长因子-A诱导的遗传性新生血管性老年性黄斑变性模型 NLRP3炎性小体失活可有效抑制新生血管的表现 损伤。这种新生血管性AMD的小鼠模型是一种与疾病特别相关的 评估NLRP3炎症小体促进机制的模型系统 炎症和病理性血管生成。 体外研究表明，自噬和TLR信号通路是重要的 NLRP3炎症体活性的调节。然而，这些途径在NLRP3中的作用 体内炎性小体激活和病理性新生血管仍不清楚。我们 提出可以利用增加自噬或抑制TLR信号来控制 NLRP3炎症体激活。在这里，我们将使用我们的新型遗传小鼠模型 新生血管AMD作为一项实验，允许精确量化新血管病变 体内模型系统确定自噬和TLR信号转导的作用 小鼠NLRP3炎性小体激活及随后的病理性血管生成 遗传方法。这些实验可能会揭示这些通路的重要性 作为NLRP3炎症小体介导的炎症的调节者。此外，我们在体内的 实验具有显著的翻译相关性，并将有助于确定 刺激自噬活性或抑制TLR信号转导是很有希望的新方法 在新生血管等情况下阻断病理性血管生成的治疗方法 AMD。

SUMMARY Pathologic neovascularization is an important aspect of the inflammatory process. NLRP3 inflammasome activation has been implicated as a major regulator of pathologic angiogenesis through secretion of proangiogenic factors (e.g. IL-1β). Targeting the NLRP3 inflammasome or its regulators may therefore represent a novel therapeutic approach to inhibit inflammation and pathologic neovascularization. For example, we could show in a novel genetic mouse model of VEGF-A-induced neovascular age-related macular degeneration (AMD) that genetic inactivation of the NLRP3 inflammasome can potently inhibit the manifestation of neovascular lesions. This mouse model of neovascular AMD serves as a particularly disease-relevant model system to assess the mechanisms through which the NLRP3 inflammasome promotes inflammation and pathologic angiogenesis. In vitro studies have suggested that autophagy and TLR-signaling pathways are important regulators of NLRP3 inflammasome activity. However, the role of these pathways for NLRP3 inflammasome activation and pathologic neovascularization in vivo remain unclear. We propose that increasing autophagy or inhibiting TLR-signaling could be utilized to control NLRP3 inflammasome activation. Here, we will use our novel genetic mouse model of neovascular AMD that allows precise quantitation of neovascular lesions as an experimental in vivo model system to determine the contributions of autophagy and TLR-signaling for NLRP3 inflammasome activation and subsequent pathologic angiogenesis using mouse genetic approaches. These experiments are likely to reveal the importance of these pathways as regulators of NLRP3 inflammasome-mediated inflammation. Moreover, our in vivo experiments have significant translational relevance and will help determine whether stimulating autophagic activity or inhibiting TLR-signaling represent promising novel therapeutic approaches to block pathologic angiogenesis in conditions such as neovascular AMD.