MDL800, a SIRT6 activator, mitigates neuroinflammation-induced retinal damage by modulating microglial M1/M2 polarization in experimental glaucoma

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling Pub Date : 2025-04-22 DOI:10.1016/j.cellsig.2025.111832

Fangyuan Hu , Daowei Zhang , Jihong Wu

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引用次数: 0

Abstract

Purpose

Glaucoma is a group of irreversible neurodegenerative disorders of the optic nerve, characterized by distinct optic nerve damage and progressive visual field loss, with its pathological foundation involving the apoptosis of retinal ganglion cells (RGCs) and axonal degeneration. Neuroinflammation driven by the polarization of retinal microglia significantly contributes to RGCs apoptosis. This study investigates the neuroprotective effects of the SIRT6 activator MDL800 on microglial polarization in experimental glaucoma.

Methods

We used a lipopolysaccharide (LPS)-induced BV2 microglial inflammation model and an ocular hypertension (OHT) rat model. The regulatory effects of MDL800 on BV2 cell M1/M2 polarization were evaluated. After inhibiting SIRT6, MDL800's impact on MAPK and AMPK-Nrf2-HO-1/NQO-1 pathways was studied. A co-culture system of BV2 cells and retinal precursor cells R28 was established to observe the effect of MDL800-regulated BV2 cell polarization on R28 cell survival. In the rat model, the effects of MDL800 on microglial polarization, retinal structure, and RGCs apoptosis in glaucoma were assessed.

Results

MDL800 facilitated BV2 cell polarization from M1 to M2 under LPS stimulation, exerting anti-inflammatory effects. It activated SIRT6 to regulate BV2 cell polarization by inhibiting the MAPK pathway and activating the AMPK-Nrf2-HO-1/NQO-1 axis. In a co-culture system of BV2 cells and R28 cells, MDL800 regulated the release of LPS-induced inflammatory factors by mediating the polarization of BV2 cells, which in turn inhibited the mitochondrial apoptotic pathway in R28 cells and promoted their survival. In the OHT rat model, MDL800 significantly inhibited retinal microglia proliferation and activation, promoted their polarization from M1 to M2, and reduced RGCs apoptosis.

Conclusions

MDL800 shows promise for clinical development and treatment of glaucoma.

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MDL800是一种SIRT6激活剂，通过调节实验性青光眼的小胶质M1/M2极化来减轻神经炎症诱导的视网膜损伤

目的青光眼是视神经的一组不可逆的神经退行性疾病，以视神经的明显损伤和进行性视野丧失为特征，其病理基础涉及视网膜神经节细胞（RGCs）的凋亡和轴突变性。视网膜小胶质细胞极化驱动的神经炎症显著促进RGCs凋亡。本研究探讨SIRT6激活剂MDL800对实验性青光眼小胶质细胞极化的神经保护作用。方法采用脂多糖（LPS）诱导的BV2小胶质细胞炎症模型和高眼压大鼠模型。观察MDL800对BV2细胞M1/M2极化的调控作用。在抑制SIRT6后，我们研究了MDL800对MAPK和AMPK-Nrf2-HO-1/NQO-1通路的影响。建立BV2细胞与视网膜前体细胞R28共培养体系，观察mdl800调控的BV2细胞极化对R28细胞存活的影响。在大鼠模型中，观察MDL800对青光眼小胶质细胞极化、视网膜结构和RGCs凋亡的影响。结果smdl800在LPS刺激下促进BV2细胞由M1向M2极化，具有抗炎作用。通过抑制MAPK通路，激活AMPK-Nrf2-HO-1/NQO-1轴，激活SIRT6调控BV2细胞极化。在BV2细胞和R28细胞共培养体系中，MDL800通过介导BV2细胞的极化调节lps诱导的炎症因子的释放，从而抑制R28细胞线粒体凋亡通路，促进R28细胞的存活。在OHT大鼠模型中，MDL800显著抑制视网膜小胶质细胞的增殖和活化，促进其从M1向M2极化，减少RGCs的凋亡。结论smdl800具有良好的青光眼临床开发和治疗前景。

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

Cellular signalling 生物-细胞生物学

CiteScore

8.40

自引率

0.00%

发文量

250

审稿时长

27 days

期刊介绍： Cellular Signalling publishes original research describing fundamental and clinical findings on the mechanisms, actions and structural components of cellular signalling systems in vitro and in vivo. Cellular Signalling aims at full length research papers defining signalling systems ranging from microorganisms to cells, tissues and higher organisms.