State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Sun Yat-Sen University, No. 7 Jinsui Road, Tianhe District, Guangzhou, 510060, Guangdong, China.
J Neuroinflammation. 2023 Apr 7;20(1):91. doi: 10.1186/s12974-023-02754-5.
Retinal ischemia-reperfusion (RIR) injury refers to an obstruction in the retinal blood supply followed by reperfusion. Although the molecular mechanism underlying the ischemic pathological cascade is not fully understood, neuroinflammation plays a crucial part in the mortality of retinal ganglion cells.
Single-cell RNA sequencing (scRNA-seq), molecular docking, and transfection assay were used to explore the effectiveness and pathogenesis of N,N-dimethyl-3β-hydroxycholenamide (DMHCA)-treated mice with RIR injury and DMHCA-treated microglia after oxygen and glucose deprivation/reoxygenation (OGD/R).
DMHCA could suppress inflammatory gene expression and attenuate neuronal lesions, restoring the retinal structure in vivo. Using scRNA-seq on the retina of DMHCA-treated mice, we provided novel insights into RIR immunity and demonstrated nerve injury-induced protein 1 (Ninjurin1/Ninj 1) as a promising treatment target for RIR. Moreover, the expression of Ninj1, which was increased in RIR injury and OGD/R-treated microglia, was downregulated in the DMHCA-treated group. DMHCA suppressed the activation of the nuclear factor kappa B (NF-κB) pathways induced by OGD/R, which was undermined by the NF-κB pathway agonist betulinic acid. Overexpressed Ninj1 reversed the anti-inflammatory and anti-apoptotic function of DMHCA. Molecular docking indicated that for Ninj1, DMHCA had a low binding energy of - 6.6 kcal/mol, suggesting highly stable binding.
Ninj1 may play a pivotal role in microglia-mediated inflammation, while DMHCA could be a potential treatment strategy against RIR injury.
视网膜缺血再灌注 (RIR) 损伤是指视网膜血液供应受阻后再灌注。虽然缺血性病理级联反应的分子机制尚未完全阐明，但神经炎症在视网膜神经节细胞死亡中起着至关重要的作用。
使用单细胞 RNA 测序 (scRNA-seq)、分子对接和转染实验，探讨 N,N-二甲基-3β-羟基胆酰胺 (DMHCA) 处理的 RIR 损伤小鼠和氧葡萄糖剥夺/再氧合 (OGD/R) 后 DMHCA 处理的小神经胶质细胞的有效性和发病机制。
DMHCA 可抑制炎症基因表达，减轻神经元损伤，恢复体内视网膜结构。在 DMHCA 处理的小鼠视网膜上进行 scRNA-seq，我们提供了 RIR 免疫的新见解，并证明神经损伤诱导蛋白 1 (Ninjurin1/Ninj 1) 是 RIR 的有前途的治疗靶点。此外，在 RIR 损伤和 OGD/R 处理的小胶质细胞中表达增加的 Ninj1 在 DMHCA 处理组中表达下调。DMHCA 抑制了 OGD/R 诱导的核因子 kappa B (NF-κB) 通路的激活，而 NF-κB 通路激动剂桦木酸则破坏了这种激活。过表达的 Ninj1 逆转了 DMHCA 的抗炎和抗凋亡作用。分子对接表明，对于 Ninj1，DMHCA 的结合能为-6.6 kcal/mol，表明结合非常稳定。
Ninj1 可能在小胶质细胞介导的炎症中发挥关键作用，而 DMHCA 可能是一种针对 RIR 损伤的潜在治疗策略。
