炎症小体激活会加重脉络膜新生血管。

IF 9.2 1区 医学 Q1 PERIPHERAL VASCULAR DISEASE Angiogenesis Pub Date : 2024-09-24 DOI:10.1007/s10456-024-09949-1
Ryan D. Makin, Ivana Apicella, Roshni Dholkawala, Shinichi Fukuda, Shuichiro Hirahara, Yoshio Hirano, Younghee Kim, Ayami Nagasaka, Yosuke Nagasaka, Siddharth Narendran, Felipe Pereira, Akhil Varshney, Shao-bin Wang, Jayakrishna Ambati, Bradley D. Gelfand
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引用次数: 0

摘要

炎症小体活化与血管异常生成疾病(如老年性黄斑变性)有关,但它在脉络膜新生血管(CNV)--晚期黄斑变性的特征性病理--中的确切作用尚不明确。有关抑制炎性体成分对 CNV 的影响的报道不尽相同,炎性体在介导病理性血管生成中的确切作用也不明确。一直以来,视网膜下注射炎性体激动剂单独用于研究视网膜色素上皮(RPE)变性,而激光光凝模型则用于研究 CNV 模型中的病理性血管生成。在这里,我们报告了同时引入几种与疾病相关的炎性体激动剂(Alu 或 B2 RNA、Alu cDNA 或寡聚淀粉样蛋白 β (1-40))会加剧激光诱导的 CNV。通过基因或药物靶向炎性体信号转导成分,包括P2rx7、Nlrp3、caspase-1、caspase-11和Myd88,以及髓系特异性caspase-1基因敲除小鼠,这些活性都会减弱或消失。Alu RNA 处理可诱导 CNV 病变内巨噬细胞中的炎性体活化,并以炎性体依赖的方式增加巨噬细胞的聚集。最后,IL-1β中和可阻止炎性体激动剂诱导的趋化、巨噬细胞迁移和血管生成。总之,这些观察结果支持炎性体刺激促进和加重 CNV 的模型,并可能成为血管生成疾病(如新生血管性 AMD)的治疗靶点。
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Inflammasome activation aggravates choroidal neovascularization

Inflammasome activation is implicated in diseases of aberrant angiogenesis such as age-related macular degeneration (AMD), though its precise role in choroidal neovascularization (CNV), a characteristic pathology of advanced AMD, is ill-defined. Reports on inhibition of inflammasome constituents on CNV are variable and the precise role of inflammasome in mediating pathological angiogenesis is unclear. Historically, subretinal injection of inflammasome agonists alone has been used to investigate retinal pigmented epithelium (RPE) degeneration, while the laser photocoagulation model has been used to study pathological angiogenesis in a model of CNV. Here, we report that the simultaneous introduction of any of several disease-relevant inflammasome agonists (Alu or B2 RNA, Alu cDNA, or oligomerized amyloid β (1–40)) exacerbates laser-induced CNV. These activities were diminished or abrogated by genetic or pharmacological targeting of inflammasome signaling constituents including P2rx7, Nlrp3, caspase-1, caspase-11, and Myd88, as well as in myeloid-specific caspase-1 knockout mice. Alu RNA treatment induced inflammasome activation in macrophages within the CNV lesion, and increased accumulation of macrophages in an inflammasome-dependent manner. Finally, IL-1β neutralization prevented inflammasome agonist-induced chemotaxis, macrophage trafficking, and angiogenesis. Collectively, these observations support a model wherein inflammasome stimulation promotes and exacerbates CNV and may be a therapeutic target for diseases of angiogenesis such as neovascular AMD.

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来源期刊
Angiogenesis
Angiogenesis PERIPHERAL VASCULAR DISEASE-
CiteScore
21.90
自引率
8.20%
发文量
37
审稿时长
6-12 weeks
期刊介绍: Angiogenesis, a renowned international journal, seeks to publish high-quality original articles and reviews on the cellular and molecular mechanisms governing angiogenesis in both normal and pathological conditions. By serving as a primary platform for swift communication within the field of angiogenesis research, this multidisciplinary journal showcases pioneering experimental studies utilizing molecular techniques, in vitro methods, animal models, and clinical investigations into angiogenic diseases. Furthermore, Angiogenesis sheds light on cutting-edge therapeutic strategies for promoting or inhibiting angiogenesis, while also highlighting fresh markers and techniques for disease diagnosis and prognosis.
期刊最新文献
Correction: Mitochondrial control of hypoxia-induced pathological retinal angiogenesis Angiogenesis is limited by LIC1-mediated lysosomal trafficking Similarities and differences between brain and skin GNAQ p.R183Q driven capillary malformations Inflammasome activation aggravates choroidal neovascularization Timed topical dexamethasone eye drops improve mitochondrial function to prevent severe retinopathy of prematurity
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