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Müller Cell Regulated Microglial Activation and Migration in Rats With N-Methyl-N-Nitrosourea-Induced Retinal
Shuai Zhang1, Shanshan Zhang1, Wenqing Gong1
1Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
Abstract:
During the pathogenesis of retinitis pigmentosa (RP), the roles of retinal microglial cells after activation have not been fully elucidated. Herein, experimental RP was induced in Sprague Dawley rats by intraperitoneal injection of N-methyl-N-nitrosourea (MNU) at 50 mg/kg, and the effects of MNU on the retinas were evaluated, respectively, by retinal histology and electroretinography recordings at serial time points. Time-dependent and gradual loss of photoreceptor cells, disrupted arrangement of the outer nuclear layer (ONL), and significant reductions in both a-wave and b-wave amplitudes were observed. Morphology changes were observed in retinal microglial cells; meanwhile, with time, the number of Iba1-positive microglia and their infiltration into the ONL gradually increased. Furthermore, physical interaction of microglial-Müller cell processes following microglial activation was observed after MNU injection. In addition, Müller cells increased CX3CL1 secretion, enhanced microglial cell migration, and upregulated the CX3CR1 expression of the latter. Our observations implied that, during the pathogenesis of RP by MNU, microglial cells exhibit a prominent morphology change and Müller cells can induce activated microglia infiltration by increasing secretion of the chemotaxis factor, CX3CL1, and promoting the migration of retinal microglial cells. This novel finding highlights a potential therapeutic target aimed at regulating the microglial response.
Insights
Retinitis pigmentosa (RP) involves retinal microglial cells and Müller cells. Müller cells secrete CX3CL1, driving microglial infiltration into damaged retinal layers, suggesting a therapeutic target.
Area of Science:
- Ophthalmology
- Neuroscience
- Cell Biology
Background:
- The role of activated retinal microglial cells in retinitis pigmentosa (RP) pathogenesis remains unclear.
- Understanding these cellular interactions is crucial for developing effective RP therapies.
Purpose of the Study:
- To elucidate the role of retinal microglial cells and their interaction with Müller cells during experimental RP.
- To investigate the molecular mechanisms underlying microglial activation and migration in RP.
Main Methods:
- Experimental RP was induced in rats using N-methyl-N-nitrosourea (MNU).
- Retinal histology, electroretinography, and immunofluorescence (Iba1) were used for evaluation.
- CX3CL1 and CX3CR1 expression levels were analyzed.
Main Results:
- MNU induced photoreceptor cell loss, outer nuclear layer disruption, and reduced electroretinogram amplitudes.
- Activated microglia (Iba1-positive) increased in number and infiltrated the outer nuclear layer.
- Müller cells secreted CX3CL1, enhancing microglial migration and CX3CR1 expression.
Conclusions:
- Müller cells promote microglial infiltration in RP pathogenesis via CX3CL1 secretion.
- Microglial activation and migration are key events in MNU-induced experimental RP.
- Targeting the Müller cell-microglia interaction presents a potential therapeutic strategy for RP.
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