Shu‑Ying Li1  · Hong Zhou1  · Guoli Zhao1,2 · Wen‑Wen Ding1  · Yu Zhang1  · Yong‑Chen Wang3  · Fang Li1  · Yanying Miao1  · Xing‑Huai Sun1,2  · Zhongfeng Wang1

1 State Key Laboratory of Brain Function and Disorders and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai 200032, China 

2 Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, NHC Key Laboratory of Myopia, Shanghai Key Laboratory of Visual Impairment and Restoration, Fudan University, Shanghai 200031, China 

3 Institute of Neuroscience and Third Affiliated Hospital, Zhengzhou University, Zhengzhou 450052, China

Abstract

Interaction between Müller cells and microglia aggravates neuroinflammation, resulting in retinal ganglion cell (RGC) death in glaucoma. Here, we investigated how tumor necrosis factor-alpha (TNF-α) produced by activated microglia mediates the crosstalk between Müller cells and microglia and impacts RGC injury in a chronic ocular hypertension (COH) glaucoma model. In COH retinas, elevated TNF-α induced the activation of Müller cells and microglia, and recruited microglia to the ganglion cell layer. Co-culture with Müller cells enhanced TNF-α-induced microglial activation, migration, and proliferation. Both in vivo and in vitro experiments confirmed that chemokine C-C motif ligand 2 (CCL2), primarily released from Müller cells, mediated the TNF-α-induced effects on microglia in COH retinas. Knockdown of CCL2 attenuated RGC damage and vision loss. Our results demonstrate that TNF-α released from microglia induces the secretion of CCL2 from Müller cells, thus inducing microglial activation and migration, exacerbating retinal neuroinflammation and RGC injury in glaucoma.

Keywords

Glaucoma; TNF-α; Müller cells; Microglia; CCL2; Neuroinflammation

[SpringerLink]