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Tumor Necrosis Factor Alpha-Mediated Interaction Between Microglia and Müller Cells Exacerbates Retinal Ganglion Cell
Shu-Ying Li1, Hong Zhou1, Guoli Zhao1,2
1State Key Laboratory of Brain Function and Disorders and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, 200032, 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.
Insights
Tumor necrosis factor-alpha (TNF-α) from microglia drives Müller cell activation and chemokine C-C motif ligand 2 (CCL2) release. This exacerbates neuroinflammation and retinal ganglion cell (RGC) death in glaucoma.
Area of Science:
- Neuroscience
- Ophthalmology
- Immunology
Background:
- Glaucoma involves neuroinflammation and retinal ganglion cell (RGC) death.
- Müller cells and microglia interactions worsen RGC injury.
Purpose of the Study:
- Investigate tumor necrosis factor-alpha (TNF-α) role in Müller cell-microglia crosstalk.
- Determine TNF-α's impact on RGC injury in a chronic ocular hypertension (COH) glaucoma model.
Main Methods:
- Utilized a chronic ocular hypertension (COH) glaucoma model.
- Performed in vivo and in vitro co-culture experiments.
- Analyzed Müller cell and microglial activation, migration, and proliferation.
- Investigated chemokine C-C motif ligand 2 (CCL2) involvement via knockdown.
Main Results:
- Elevated TNF-α in COH retinas activated Müller cells and microglia, recruiting microglia.
- Müller cells enhanced TNF-α-induced microglial activation, migration, and proliferation.
- CCL2, released by Müller cells, mediated TNF-α effects on microglia.
- CCL2 knockdown attenuated RGC damage and vision loss.
Conclusions:
- Microglial TNF-α induces Müller cell CCL2 secretion.
- This crosstalk exacerbates neuroinflammation and RGC injury in glaucoma.
- Targeting the TNF-α/CCL2 pathway may offer therapeutic benefits for glaucoma.
