Tissue & cell · 2026
FFAs secreted by A1 astrocytes contribute to RGCs apoptosis via PERK/eIF2α/ATF4/CHOP pathway in retinal ischemia/reperfusion injury.
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Shi Wenjia, Liu Can, Yang Jiangcheng, Qin Liangshi, Liao Junle, Huang Jufang, Gao Zhaolin, Chen Dan
Аннотация
PURPOSE: To explore the specific mechanisms of retinal neuronal apoptosis induced by A1 polarization of astrocytes under retinal ischemia/reperfusion (RI/R) injury.
METHODS: 1) In vivo, SD rats were selected for acute intraocular hypertension (AIH) model. In vitro, A1 astrocytes model was induced by the tumor necrosis factor α (TNF-α), interleukin-1α (IL-1α) and complement 1q (C1q) and oxygen and glucose deprivation/recovery (OGD/R) model of R28 cells. 2) Immunofluorescence was used to assess the expression of GFAP, C3, S100A10 and ELOVL1 genes morphologically. Apoptotic cell death was assessed by TUNEL and PI staining. 3) Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to detect the mRNA expression levels of inflammatory factors. 4) The expression levels of GFAP、C3、S100A10、ELOVL1、p-PERK、p-eIF2α、ATF4、CHOP、Bax and Bcl-2 were measured by western blot (WB) assay. 5) The relative content of long-chain saturated free fatty acids (FFAs) in astrocyte medium was measured by lipidomic sequencing.
RESULTS: 1) Retinal astrocytes polarized to neurotoxic A1 phenotype after RI/R injury. 2) Compared to normal astrocytes, the release of long-chain saturated FFAs from A1 astrocytes increased. The inhibition of the production of saturated FFAs could significantly inhibit neuronal apoptosis. 3) A1 Astrocytes conditioned medium induced neuronal apoptosis by activating the PERK/eIF2α/ATF4/CHOP signaling pathway.
CONCLUSION: Under conditions of RI/R injury, retinal astrocytes polarized to A1 phenotype and secreted long-chain saturated FFAs, which mediated ER stress via the PERK/eIF2α/ATF4/CHOP pathway and finally caused retinal neuronal apoptosis.
METHODS: 1) In vivo, SD rats were selected for acute intraocular hypertension (AIH) model. In vitro, A1 astrocytes model was induced by the tumor necrosis factor α (TNF-α), interleukin-1α (IL-1α) and complement 1q (C1q) and oxygen and glucose deprivation/recovery (OGD/R) model of R28 cells. 2) Immunofluorescence was used to assess the expression of GFAP, C3, S100A10 and ELOVL1 genes morphologically. Apoptotic cell death was assessed by TUNEL and PI staining. 3) Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to detect the mRNA expression levels of inflammatory factors. 4) The expression levels of GFAP、C3、S100A10、ELOVL1、p-PERK、p-eIF2α、ATF4、CHOP、Bax and Bcl-2 were measured by western blot (WB) assay. 5) The relative content of long-chain saturated free fatty acids (FFAs) in astrocyte medium was measured by lipidomic sequencing.
RESULTS: 1) Retinal astrocytes polarized to neurotoxic A1 phenotype after RI/R injury. 2) Compared to normal astrocytes, the release of long-chain saturated FFAs from A1 astrocytes increased. The inhibition of the production of saturated FFAs could significantly inhibit neuronal apoptosis. 3) A1 Astrocytes conditioned medium induced neuronal apoptosis by activating the PERK/eIF2α/ATF4/CHOP signaling pathway.
CONCLUSION: Under conditions of RI/R injury, retinal astrocytes polarized to A1 phenotype and secreted long-chain saturated FFAs, which mediated ER stress via the PERK/eIF2α/ATF4/CHOP pathway and finally caused retinal neuronal apoptosis.