Neutrophils promote laser-induced choroidal neovascularization by increasing pro-inflammatory cytokines secretion and cell cycle arrest in retinal pigment epithelium

IF 4.8 2区 医学 Q2 IMMUNOLOGY
Qian Fan , Xian Song , Mengyao Li , Qian Xu , Chenfei Yan , Haiming Li , Yi Qu
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Abstract

Inflammation is hypothesized to have essential functions in the development of wet age-related macular degeneration (AMD). Polymorphonuclear neutrophils (PMNs), recognized as major players in inflammation, are typically the first leukocytes to be recruited to an inflammatory site. Previous studies have identified neutrophil aggregates in the lesion site of the choroidal neovascularization model, and systemic depletion of neutrophils in adult mice is associated with reduced choroidal neovascularization (CNV) area, suggesting a pivotal role of PMNs in CNV pathogenesis. Here, we investigate the role of neutrophils in promoting CNV, a key feature of wet AMD. The malfunction and demise of retinal pigment epithelium cells are essential elements in CNV pathogenesis. Our hypothesis posits that neutrophils exacerbate CNV by influencing pro-inflammatory cytokines secreted by retinal pigment epithelium (RPE) cells. Using in vivo laser-induced CNV models with mice and in vitro experiments with the human ARPE-19 cell line, we demonstrated that co-culturing neutrophils with ARPE-19 cells induces an increase in pro-inflammatory cytokines and leads to S-phase cell cycle arrest, potentially through the induction of double-strand breaks (DSBs). Further exploration of this interaction revealed a potential pathway involving reactive oxygen species (ROS) and microRNA-23a, wherein PMNs induce DSBs by initiating the downregulation of LB1 via microRNA-23a. Additionally, we found that dHL-60 cell line could serve as a substitute for primary PMNs, highlighting its potential as a valuable tool in experimental models involving interactions with retinal cells. Our findings underscore the significant role of neutrophils in CNV pathogenesis, providing insights into potential therapeutic targets for wet AMD.

Abstract Image

中性粒细胞通过增加促炎细胞因子的分泌和视网膜色素上皮细胞周期阻滞来促进激光诱导的脉络膜新生血管。
炎症被假设在湿性年龄相关性黄斑变性(AMD)的发展中具有基本功能。多形核中性粒细胞(pmn)被认为是炎症的主要参与者,通常是第一个被招募到炎症部位的白细胞。先前的研究发现,中性粒细胞聚集在脉络膜新生血管模型的病变部位,成年小鼠全身中性粒细胞耗损与脉络膜新生血管(CNV)区域减少有关,提示PMNs在CNV发病中起关键作用。在这里,我们研究了中性粒细胞在促进CNV中的作用,CNV是湿性AMD的一个关键特征。视网膜色素上皮细胞的功能障碍和死亡是CNV发病的重要因素。我们的假设假设中性粒细胞通过影响视网膜色素上皮(RPE)细胞分泌的促炎细胞因子而加剧CNV。利用小鼠体内激光诱导的CNV模型和人类ARPE-19细胞系的体外实验,我们证明中性粒细胞与ARPE-19细胞共培养可诱导促炎细胞因子的增加,并可能通过诱导双链断裂(DSBs)导致s期细胞周期阻滞。对这种相互作用的进一步探索揭示了一个涉及活性氧(ROS)和microRNA-23a的潜在途径,其中PMNs通过microRNA-23a启动LB1的下调来诱导dsb。此外,我们发现dHL-60细胞系可以作为原代pmn的替代品,突出了其作为与视网膜细胞相互作用的实验模型的有价值工具的潜力。我们的发现强调了中性粒细胞在CNV发病机制中的重要作用,为湿性AMD的潜在治疗靶点提供了见解。
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来源期刊
CiteScore
8.40
自引率
3.60%
发文量
935
审稿时长
53 days
期刊介绍: International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.
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