Tang Xiangcheng, Liu Wei, Liang Jia, Zhu Xingfei, Ge Xiangyu, Fang Dong, Ling Lirong, Yuan Fanglan, Zeng Kun, Chen Qingshan, Zhang Guoming, Gong Lili, Zhang Shaochong
Shenzhen Eye Hospital, Shenzhen Eye Institute, JinanUniversity, 18 Zetian Road, Shenzhen, 518040, Guangdong, China.
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, 510060, Guangdong, China.
Inflammation. 2024 Dec 27. doi: 10.1007/s10753-024-02224-x.
Microglia are highly specialized resident macrophages in the central nervous system that play a pivotal role in modulating neuroinflammation. Microglial plasticity is essential for their function, allowing them to polarize into proinflammatory M1-like or anti-inflammatory M2-like phenotypes. However, the mechanisms driving M1 and M2 microglial induction during retinal degeneration remain largely unexplored. In addition, drugs that regulate retinal microglial polarity have not been fully investigated. The synthetic glucocorticoid triamcinolone acetonide (TA) is widely utilized in ophthalmology clinics for its anti-inflammatory properties. Here, we investigated microglial polarity in a light-induced retinal degeneration mouse model, along with the effects and mechanisms of intravitreal injection of TA on microglial polarity, retinal inflammation, and visual function following light damage (LD). Our findings demonstrated that LD induced a pro-inflammatory M1 microglial signature, with levels of M1 marker proteins in the retina increasing in a time-dependent manner following LD. Intravitreal TA treatment mitigated LD-induced retinal inflammation, photoreceptor death, and retinal blood vessel leakage, and preserved retinal responsiveness to light stimuli. Mechanistically, TA suppressed the proinflammatory microglial phenotype while promoting the anti-inflammatory phenotype by activating the signal transducer and activator of transcription 6/arginase1 (STAT6/Arg1) signaling pathway. These results reveal a new mechanism by which TA protects the retina from LD by shifting microglia toward an anti-inflammatory state through the STAT6/Arg1 axis.
小胶质细胞是中枢神经系统中高度特化的常驻巨噬细胞，在调节神经炎症中起关键作用。小胶质细胞的可塑性对其功能至关重要，使其能够极化为促炎的M1样或抗炎的M2样表型。然而，在视网膜变性过程中驱动M1和M2小胶质细胞诱导的机制在很大程度上仍未被探索。此外，调节视网膜小胶质细胞极性的药物尚未得到充分研究。合成糖皮质激素曲安奈德（TA）因其抗炎特性而在眼科临床中广泛应用。在此，我们研究了光诱导的视网膜变性小鼠模型中的小胶质细胞极性，以及玻璃体内注射TA对光损伤（LD）后小胶质细胞极性、视网膜炎症和视觉功能的影响及机制。我们的研究结果表明，LD诱导了促炎的M1小胶质细胞特征，LD后视网膜中M1标记蛋白的水平呈时间依赖性增加。玻璃体内TA治疗减轻了LD诱导的视网膜炎症、光感受器死亡和视网膜血管渗漏，并保留了视网膜对光刺激的反应性。从机制上讲，TA通过激活信号转导和转录激活因子6/精氨酸酶1（STAT6/Arg1）信号通路抑制促炎小胶质细胞表型，同时促进抗炎表型。这些结果揭示了一种新机制，即TA通过STAT6/Arg1轴使小胶质细胞向抗炎状态转变，从而保护视网膜免受LD损伤。
