CSF1R-dependent microglia depletion mitigates neuroinflammation and photoreceptor loss in MNU-induced retinal degenerationOA
Background:Microglial activation is a hallmark of retinal neurodegeneration.However,whether microglia predominantly drive inflammatory damage or support tissue adaptation after acute photoreceptor injury remains unclear.Resolving this issue is critical for defining therapeutic strategies.As colony-stimulating factor 1 receptor(CSF1R)signaling is essential for microglial survival,its pharmacological inhibition enables selective microglial depletion in vivo.Here,we used the CSF1R inhibitor PLX5622 in the N-methyl-N-nitrosourea(MNU)model to directly test the contribution of microglia to inflammation and photoreceptor degeneration.Methods:C57BL/6J mice received PLX5622 for 14 days before and throughout a 5-day MNU regimen.Retinal structure was assessed by fundus photography,optical coherence tomography(OCT),and hematoxylin and eosin(H&E)histology.Visual function was evaluated via electroretinography(ERG).Global transcriptomic alterations were profiled by RNA-seq,and selected inflammatory and complement mediators were assessed by Western blot.Results:PLX5622 treatment resulted in near-complete depletion of TMEM119+/Iba1+microglia in MNU-injured retinas.Microglia depletion was associated with reduced fundus white lesions,preserved outer nuclear layer(ONL)thickness and nuclei density,and significantly rescued ERG a-and b-wave amplitudes.Transcriptomic analysis further revealed broad attenuation of pro-inflammatory and innate immune pathways,accompanied by modulation of antioxidant responses,mitochondrial/metabolic alterations,neuron-related signaling,and macroglial activation-related programs.Consistently,Western blot analysis confirmed that MNU-induced upregulation of IL-1β,C3,and C1qa was markedly reduced following PLX5622 treatment.Conclusions:Pharmacological CSF1R inhibition leading to efficient retinal microglial depletion attenuated neuroinflammatory responses and preserved photoreceptor structure and visual function in acute toxic retinal degeneration.These findings indicate that microglial activation functions predominantly as a pathogenic amplifier rather than an adaptive response in this context,and identify CSF1R-dependent myeloid signaling as a key mechanistic driver of injury-associated retinal degeneration.
Hong Zhou;Biyan Ni;Tian Zhou;Ziqi Yang;Yang Zhou;Jingpeng Li;Minglu Ma;Huaicheng Wang;Peng An;Qingbo Guo;Xiaojing Lin;Shiya Lin;Huiyi Xu;Xialin Liu;Chang He
State Key Laboratory of Ophthalmology,Zhongshan Ophthalmic Center,Sun Yat-sen University,Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science,Guangzhou 510060,ChinaState Key Laboratory of Ophthalmology,Zhongshan Ophthalmic Center,Sun Yat-sen University,Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science,Guangzhou 510060,China Department of Ophthalmology,The First Affiliated Hospital of Nanjing Medical University,Nanjing 210029,ChinaState Key Laboratory of Ophthalmology,Zhongshan Ophthalmic Center,Sun Yat-sen University,Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science,Guangzhou 510060,ChinaState Key Laboratory of Ophthalmology,Zhongshan Ophthalmic Center,Sun Yat-sen University,Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science,Guangzhou 510060,ChinaState Key Laboratory of Ophthalmology,Zhongshan Ophthalmic Center,Sun Yat-sen University,Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science,Guangzhou 510060,ChinaState Key Laboratory of Ophthalmology,Zhongshan Ophthalmic Center,Sun Yat-sen University,Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science,Guangzhou 510060,ChinaState Key Laboratory of Ophthalmology,Zhongshan Ophthalmic Center,Sun Yat-sen University,Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science,Guangzhou 510060,ChinaState Key Laboratory of Ophthalmology,Zhongshan Ophthalmic Center,Sun Yat-sen University,Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science,Guangzhou 510060,ChinaState Key Laboratory of Ophthalmology,Zhongshan Ophthalmic Center,Sun Yat-sen University,Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science,Guangzhou 510060,ChinaState Key Laboratory of Ophthalmology,Zhongshan Ophthalmic Center,Sun Yat-sen University,Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science,Guangzhou 510060,ChinaState Key Laboratory of Ophthalmology,Zhongshan Ophthalmic Center,Sun Yat-sen University,Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science,Guangzhou 510060,ChinaState Key Laboratory of Ophthalmology,Zhongshan Ophthalmic Center,Sun Yat-sen University,Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science,Guangzhou 510060,ChinaState Key Laboratory of Ophthalmology,Zhongshan Ophthalmic Center,Sun Yat-sen University,Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science,Guangzhou 510060,ChinaState Key Laboratory of Ophthalmology,Zhongshan Ophthalmic Center,Sun Yat-sen University,Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science,Guangzhou 510060,ChinaState Key Laboratory of Ophthalmology,Zhongshan Ophthalmic Center,Sun Yat-sen University,Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science,Guangzhou 510060,China
医药卫生
microgliaCSF1R inhibitionretinal degenerationphotoreceptor injuryneuroinflammation
《Eye Science》 2026 (2)
P.89-100,12
supported by National Natural Science Foundation of China(82322016,82271095)Guangdong Provincial Key Area R&D Program(2023B1111050004)Natural Science Foundation of Guangdong Province,China(2023A1515012656)Guangzhou Science and Technology Plan Project(2025A03J3981,2024B01J1121,2025A03J3988).
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