Ganglion cell-derived LysoPS induces retinal neovascularisation by activating the microglial GPR34-PI3K-AKT-NINJ1 axis.

IF 9.3 1区医学 Q1 IMMUNOLOGY

Journal of Neuroinflammation Pub Date : 2024-10-28 DOI:10.1186/s12974-024-03265-7

Lushu Chen, HuiYing Zhang, Ying Zhang, Xiumiao Li, MeiHuan Wang, Yaming Shen, Yuan Cao, Yong Xu, Jin Yao

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引用次数: 0

Abstract

Retinal neovascularisation is a major cause of blindness in patients with proliferative diabetic retinopathy (PDR). It is mediated by the complex interaction between dysfunctional ganglion cells, microglia, and vascular endothelial cells. Notably, retinal microglia, the intrinsic immune cells of the retina, play a crucial role in the pathogenesis of retinopathy. In this study, we found that lysophosphatidylserines (LysoPS) released from injured ganglion cells induced microglial extracellular trap formation and retinal neovascularisation. Mechanistically, LysoPS activated the GPR34-PI3K-AKT-NINJ1 signalling axis by interacting with the GPR34 receptor on the microglia. This activation upregulated the expression of inflammatory cytokines, such as IL-6, IL-8, VEGFA, and FGF2, and facilitated retinal vascular endothelial cell angiogenesis. As a result, inhibition of the GPR34-PI3K-AKT-NINJ1 axis significantly decreased microglial extracellular trap formation and neovascularisation by suppressing LysoPS-induced microglial inflammatory responses, both in vitro and in vivo. This study reveals the crucial role of apoptotic ganglion cells in activating microglial inflammation in PDR, thereby enhancing our understanding of the pathogenesis of retinal neovascularisation.

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神经节细胞衍生的 LysoPS 通过激活小胶质细胞 GPR34-PI3K-AKT-NINJ1 轴诱导视网膜新生血管。

视网膜新生血管是增生性糖尿病视网膜病变（PDR）患者失明的主要原因。它是由功能失调的神经节细胞、小胶质细胞和血管内皮细胞之间复杂的相互作用介导的。值得注意的是，视网膜小胶质细胞是视网膜固有的免疫细胞，在视网膜病变的发病机制中起着至关重要的作用。在这项研究中，我们发现受伤的神经节细胞释放的溶血磷脂酰丝氨酸（LysoPS）会诱导小胶质细胞胞外陷阱的形成和视网膜新生血管的形成。从机制上讲，LysoPS 通过与小胶质细胞上的 GPR34 受体相互作用，激活了 GPR34-PI3K-AKT-NINJ1 信号轴。这种激活会上调炎性细胞因子（如 IL-6、IL-8、VEGFA 和 FGF2）的表达，并促进视网膜血管内皮细胞的血管生成。因此，抑制 GPR34-PI3K-AKT-NINJ1 轴可通过抑制 LysoPS 诱导的小胶质细胞炎症反应，在体外和体内显著减少小胶质细胞胞外陷阱的形成和新生血管的形成。这项研究揭示了凋亡的神经节细胞在激活 PDR 中的小胶质细胞炎症中的关键作用，从而加深了我们对视网膜新生血管发病机制的理解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Neuroinflammation 医学-神经科学

CiteScore

15.90

自引率

3.20%

发文量

276

审稿时长

1 months

期刊介绍： The Journal of Neuroinflammation is a peer-reviewed, open access publication that emphasizes the interaction between the immune system, particularly the innate immune system, and the nervous system. It covers various aspects, including the involvement of CNS immune mediators like microglia and astrocytes, the cytokines and chemokines they produce, and the influence of peripheral neuro-immune interactions, T cells, monocytes, complement proteins, acute phase proteins, oxidative injury, and related molecular processes. Neuroinflammation is a rapidly expanding field that has significantly enhanced our knowledge of chronic neurological diseases. It attracts researchers from diverse disciplines such as pathology, biochemistry, molecular biology, genetics, clinical medicine, and epidemiology. Substantial contributions to this field have been made through studies involving populations, patients, postmortem tissues, animal models, and in vitro systems. The Journal of Neuroinflammation consolidates research that centers around common pathogenic processes. It serves as a platform for integrative reviews and commentaries in this field.