Interplay between Müller cells and microglia aggravates retinal inflammatory response in experimental glaucoma

Hu, Xin; Zhao, Guoli; Xu, Meng-Xi; Zhou, Han; Li, Fang; Miao, Yanying; Yang, Xiong-Li; Wang, Zhongfeng

doi:10.1186/s12974-021-02366-x

Cited by 55 publications

(46 citation statements)

References 54 publications

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“…Similar results have been described in diabetic retinopathy ( Li et al, 2019 ), where the SFN protection over the Müller cells was associated with the activation of the Nrf2 pathway and the inhibition of the inflammasome. Moreover, the interplay between Müller cells and microglia has been described in eye pathologies, by which the activation of both glial cells induces continuous activation feedback ( Hu et al, 2021 ). A direct SFN effect over the Müller cells or an indirect effect through the microglia SFN modulation should be considered as underlying mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Sulforaphane Modulates the Inflammation and Delays Neurodegeneration on a Retinitis Pigmentosa Mice Model

et al. 2022

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The term retinitis pigmentosa (RP) describes a large group of hereditary retinopathies. From a cellular view, retinal degeneration is prompted by an initial death of rods, followed later by cone degeneration. This cellular progressive degeneration is translated clinically in tunnel vision, which evolves to complete blindness. The mechanism underlying the photoreceptor degeneration is unknown, but several mechanisms have been pointed out as main co-stars, inflammation being one of the most relevant. Retinal inflammation is characterized by proliferation, migration, and morphological changes in glial cells, in both microglia and Müller cells, as well as the increase in the expression of inflammatory mediators. Retinal inflammation has been reported in several animal models and clinical cases of RP, but the specific role that inflammation plays in the pathology evolution remains uncertain. Sulforaphane (SFN) is an antioxidant natural compound that has shown anti-inflammatory properties, including the modulation of glial cells activation. The present work explores the effects of SFN on retinal degeneration and inflammation, analyzing the modulation of glial cells in the RP rd10 mice model. A daily dose of 20 mg/kg of sulforaphane was administered intraperitoneally to control (C57BL/6J wild type) and rd10 (Pde6brd10) mice, from postnatal day 14 to day 20. On postnatal day 21, euthanasia was performed. Histological retina samples were used to assess cellular degeneration, Müller cells, and microglia activation. SFN administration delayed the loss of photoreceptors. It also ameliorated the characteristic reactive gliosis, assessed by retinal GFAP expression. Moreover, sulforaphane treatment regulated the microglia activation state, inducing changes in the microglia morphology, migration, and expression through the retina. In addition, SFN modulated the expression of the interleukins 1β, 4, Ym1, and arginase inflammatory mediators. Surprisingly, M2 polarization marker expression was increased at P21 and was reduced by SFN treatment. To summarize, SFN administration reduced retinal neurodegeneration and modified the inflammatory profile of RP, which may contribute to the SFN neuroprotective effect.

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Section: Discussionmentioning

confidence: 99%

Sulforaphane Modulates the Inflammation and Delays Neurodegeneration on a Retinitis Pigmentosa Mice Model

et al. 2022

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“…Activated Müller cells could induce microglia activation and the interaction of Müller cells and microglia aggravated retinal inflammatory response, which contributed to RGC injury in COH retina (Hu et al, 2021). Based on the present results and our previous study (Cheng et al, 2021; Hu et al, 2021; Xu et al, 2020), we speculate that at the early stage of IOP elevation, inhibition of the reverse signaling could rescue GLAST downregulation and attenuate Müller cell gliosis, thus relieving the activation of retinal glial cells and reducing retinal inflammatory response, which indirectly contribute to reduction of RGC apoptosis. On the other hand, inhibition of the forward signaling in RGCs may directly attenuate RGC apoptosis (Xu et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

EphA4/ephrinA3 reverse signaling mediated downregulation of glutamate transporter GLAST in Müller cells in an experimental glaucoma model

Wang

Cheng

et al. 2022

Glia

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Deficiency of glutamate transporter GLAST in Müller cells may be culpable for excessive extracellular glutamate, which involves in retinal ganglion cell (RGC) damage in glaucoma. We elucidated how GLAST was regulated in rat chronic ocular hypertension (COH) model. Western blot and whole-cell patch-clamp recordings showed that GLAST proteins and GLAST-mediated current densities in Müller cells were downregulated at the early stages of COH. In normal rats, intravitreal injection of the ephrinA3 activator EphA4-Fc mimicked the changes of GLAST in COH retinas. In purified cultured Müller cells, EphA4-Fc treatment reduced GLAST expression at mRNA and protein levels, which was reversed by the tyrosine kinase inhibitor PP2 or transfection with ephrinA3-siRNA (Si-EFNA3), suggesting that EphA4/ephrinA3 reverse signaling mediated GLAST downregulation.EphA4/ephrinA3 reverse signaling-induced GLAST downregulation was mediated by inhibiting PI3K/Akt/NF-κB pathways since EphA4-Fc treatment of cultured Müller cells reduced the levels of p-Akt/Akt and NF-κB p65, which were reversed by transfecting Si-EFNA3. In Müller cells with ephrinA3 knockdown, the PI3K inhibitor LY294002 still decreased the protein levels of NF-κB p65 in the presence of EphA4-Fc, and the mRNA levels of GLAST were reduced by LY294002 and the NF-κB inhibitor SN50, respectively. Pre-injection of the PI3K/Akt pathway activator 740 Y-P reversed the GLAST downregulation in COH retinas. Western blot and TUNEL staining showed that transfecting of Si-EFNA3 reduced Müller cell gliosis and RGC apoptosis in COH retinas. Our results suggest that activated EphA4/ephrinA3 reverse signaling induces GLAST downregulation in Müller cells via inhibiting PI3K/Akt/NF-κB pathways, thus contributing to RGC damage in glaucoma.

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“…Next, we established an in vitro model using mouse microglia subjected to 2 mM ATP, which activates P2X7R, to mimic COH. The concentration of ATP refers to previous literatures [31,41,48,49]. However, due to the limited number of primary mouse retinal microglia, which was not enough to provide cells required for the entire experiments, we only used primary microglia to verify that P2X7R activation could induce autophagy and pyroptosis by western blot, as shown in supplemental gure 1C.…”

Section: Atp-treated Induce Altered Autophagy and Pyroptosis In Cultu...mentioning

confidence: 99%

Crosstalk Between Autophagy and Pyroptosis of Microglia contributes to Retinal Ganglion Cells Damage in Chronic Ocular Hypertension

Huang

Zhang

et al. 2022

Preprint

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BACKGROUND. Glaucoma is a group of neurodegenerative diseases characterized by the damage of retinal ganglion cells (RGCs). Chronic ocular hypertension (COH) as one of the critical risk factors of glaucoma, the mechanisms of COH-induced RGCs damage has not been clarified. In recent years, studies have reported altered levels of autophagy and pyroptosis in glaucomatous microglia. However, it is unclear whether autophagy and pyroptosis of microglia are related and whether this relationship mediates COH-induced RGCs damage.METHODS. A mouse COH experimental glaucomatous model in vivo was established. Besides, we used 2 mmol/L (mM) ATP-treated microglia to simulate COH in vitro. Western blot, enzyme-linked immunosorbent assay, immunofluorescence and electron microscopy were employed to detect the exact relationship between autophagy and pyroptosis of microglia. Moreover, we utilized co-cultivation, live/dead viability assay, neutralizing antibody treatment and intra-vitreous injection to investigate the role of this relationship of microglia in COH-induced RGCs damage.RESULTS. In COH model in vivo, a transient boost of autophagy and a gradual increase of pyroptosis were observed. And the consistent phenomena were also found in ATP-treated microglia in vitro. We next observed that inhibition of the P2X7R-NLRP3-CASP1-GSDMD pathway and activation of autophagy could attenuate pyroptosis of microglia, thereby counteracting the RGCs damage induced by COH in vivo and ATP in vitro. The intricate molecular mechanism between pyroptosis mediated by the above pathway and autophagy is referred as “crosstalk” in this paper. Furthermore, we revealed the indispensable significance of interleukin-1β (IL-1β) in microglia-mediated RGCs damage.CONCLUSIONS. Our findings show that the crosstalk between autophagy and pyroptosis of microglia in COH can be achieved through P2X7R-NLRP3 pathway. Moreover, intervening in the crosstalk effectively counteracts COH-induced RGCs damage. Our results provide new insights into developing therapies for glaucoma based on the concept of neuroinflammation.

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Interplay between Müller cells and microglia aggravates retinal inflammatory response in experimental glaucoma

Cited by 55 publications

References 54 publications

Sulforaphane Modulates the Inflammation and Delays Neurodegeneration on a Retinitis Pigmentosa Mice Model

Sulforaphane Modulates the Inflammation and Delays Neurodegeneration on a Retinitis Pigmentosa Mice Model

EphA4/ephrinA3 reverse signaling mediated downregulation of glutamate transporter GLAST in Müller cells in an experimental glaucoma model

Crosstalk Between Autophagy and Pyroptosis of Microglia contributes to Retinal Ganglion Cells Damage in Chronic Ocular Hypertension

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