Progranulin released from microglial lysosomes reduces neuronal ferroptosis after cerebral ischemia in mice

Chen, Tingting; Shi, Rubing; Suo, Qian; Wu, Shukun; Liu, Chang; Huang, Shuxian; Khan, Haroon Latif; Liu, Ze; He, Yuyan; Huang, Tian; Wang, Yongting; Tang, Yaohui; Yang, Guo‐Yuan; Zhang, Zhijun

doi:10.1177/0271678x221145090

Cited by 13 publications

(4 citation statements)

References 63 publications

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“…Sample sizes for animal studies were determined by a two-sided power analysis for the primary parameter with mean differences and standard deviations based on similar previously published results (power ¼ 80%, a ¼ 0.05). 24,25 All statistics were performed using Prism GraphPad 9 (GraphPad Software, San Diego, CA). Results were presented as meanAEstandard deviation (SD).…”

Section: Discussionmentioning

confidence: 99%

CCL5 mediated astrocyte-T cell interaction disrupts blood-brain barrier in mice after hemorrhagic stroke

Zhou,

Liu,

Wang

et al. 2023

J Cereb Blood Flow Metab

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The crosstalk between reactive astrocytes and infiltrated immune cells plays a critical role in maintaining blood-brain barrier (BBB) integrity. However, how astrocytes interact with immune cells and the effect of their interaction on BBB integrity after hemorrhagic stroke are still unclear. By performing RNA sequencing in astrocytes that were activated by interleukin-1α (IL-1α), tumor necrosis factor α (TNFα), and complement component 1q (C1q) treatment, we found CCL5 was among the top upregulated genes. Immunostaining and western blot results demonstrated that CCL5 was increased in mice brain after hemorrhagic stroke. Flow cytometry showed that knockout of astrocytic CCL5 reduced the infiltration of CD8+ but not CD4+ T and myeloid cells into the brain ( p < 0.05). In addition, knockout CCL5 in astrocytes increased tight junction-related proteins ZO-1 and Occludin expression; reduced Evans blue leakage, perforin and granzyme B expression; improved neurobehavioral outcomes in hemorrhagic stroke mice ( p < 0.05), while transplantation of CD8+ T cells reversed these protective effects. Moreover, co-culture of CD8+ T cells with bEnd.3 cells induced the apoptosis of bEnd.3 cells, which was rescued by inhibiting perforin. In conclusion, our study suggests that CCL5 mediated crosstalk between astrocytes and CD8+ T cells represents an important therapeutic target for protecting BBB in stroke.

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Section: Discussionmentioning

confidence: 99%

CCL5 mediated astrocyte-T cell interaction disrupts blood-brain barrier in mice after hemorrhagic stroke

Zhou,

Liu,

Wang

et al. 2023

J Cereb Blood Flow Metab

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“…Recently, Ting Chen et al. reported that PGRN upregulation attenuated ferroptosis by decreasing malondialdehyde and increasing Gpx4, Nrf2, and Slc7a11 expression and glutathione levels in microglia ( 31 ). Although the function of PGRN in the progression of RA is not fully understood, we can speculate that PGRN may influence RA progression by attenuating ferroptosis.…”

Section: Discussionmentioning

confidence: 99%

“…Increased risk of RA and joint destruction in PGRN -/mice model of collageninduced arthritis compared to controls, and inflammatory arthritis can be revered by the administration of PGRN (25,29,30). Recently, Ting Chen et al reported that PGRN upregulation attenuated ferroptosis by decreasing malondialdehyde and increasing Gpx4, Nrf2, and Slc7a11 expression and glutathione levels in microglia (31). Although the function of PGRN in the progression of RA is not fully understood, we can speculate that PGRN may influence RA progression by attenuating ferroptosis.…”

Section: Discussionmentioning

confidence: 99%

Identification of potential ferroptosis-associated biomarkers in rheumatoid arthritis

Zhang

Gong

et al. 2023

Front. Immunol.

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BackgroundRheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by inflammation and gradual joint degeneration, resulting in function disability. Recently, ferroptosis, a novel form of regulated cell death that involves iron-dependent lipid peroxidation, has been implicated in the pathogenesis of RA. However, the underlying molecular mechanisms and key genes involved in ferroptosis in RA remain largely unknown.MethodsThe GSE134420 and GSE77298 datasets were downloaded and DEGs were identified using R software. The DEGs were then mapped to the dataset of 619 ferroptosis-related genes obtained from the GeneCards database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted to investigate the possible biological functions. Protein-protein interaction (PPI) networks were constructed to identify the hub genes. The relationship between hub genes and immune infiltration was estimated using the CIBERSORT algorithms. Gene Set Enrichment Analysis (GSEA) was used to explore the underlying signaling pathways of hub genes. Genome-wide association studies (GWAS) analysis was performed to confirm the pathogenic regions of the hub genes. RcisTarget and Gene-motif ranking databases were used to identify transcription factors (TFs) associated with the hub genes. The miRcode databases were utilized to construct the microRNA (miRNA)-messenger RNA (mRNA) network. Single-cell analysis was utilized to cluster cells and display the expression of hub genes in cell clusters. Finally, the expression and potential mechanism of hub genes were investigated in human and experimental samples.ResultsThree hub genes PTGS2, ENO1, and GRN highly associated with ferroptosis were identified. Four pathogenic genes HLA-B, MIF, PSTPIP, TLR1 were identified that were significantly and positively correlated with the expression levels of hub genes. The results of the GSEA showed that the hub genes were significantly enriched in pathways related to immunity, lysosome, phagocytosis and infection. ENO1 and PTGS2 were enriched in the TF-binding motif of cisbp_M5493. The hub genes were validated in experimental and patient samples and highly level of ENO1 expression was found to inhibit ACO1, which reduces ferroptosis in proliferating fibroblast-like synoviocytes (FLS).ConclusionPTGS2, ENO1 and GRN were identified and validated as potential ferroptosis-related biomarkers. Our work first revealed that ENO1 is highly expressed in RA synovium and that ferroptosis may be regulated by the ENO1-ACO1 axis, advancing the understanding of the underlying ferroptosis-related mechanisms of synovial proliferation and providing potential diagnostic and therapeutic targets for RA.

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“…While most studies support the pro-ferroptotic role of lysosomes, specific lysosomal proteins or degradation products, such as cysteine and selenium, can also exert inhibitory effects on ferroptosis. GRN (granulin precursor), derived from microglial lysosomes, inhibits ferroptosis-mediated neuronal injury by upregulating the expression of GPX4, NFE2L2, and SLC7A11 [ 192 ]. In contrast, the knockdown of LAMP2A , a receptor for CMA, induces ferroptosis in retinal pigment epithelial cells by depleting cytosolic cysteine and GSH levels [ 193 ].…”

Section: Role Of Lysosomes In Ferroptosismentioning

confidence: 99%

International consensus guidelines for the definition, detection, and interpretation of autophagy-dependent ferroptosis

Chen,

Tsvetkov,

Shen

et al. 2024

Autophagy

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Macroautophagy/autophagy is a complex degradation process with a dual role in cell death that is influenced by the cell types that are involved and the stressors they are exposed to. Ferroptosis is an iron-dependent oxidative form of cell death characterized by unrestricted lipid peroxidation in the context of heterogeneous and plastic mechanisms. Recent studies have shed light on the involvement of specific types of autophagy (e.g. ferritinophagy, lipophagy, and clockophagy) in initiating or executing ferroptotic cell death through the selective degradation of anti-injury proteins or organelles. Conversely, other forms of selective autophagy (e.g. reticulophagy and lysophagy) enhance the cellular defense against ferroptotic damage. Dysregulated autophagy-dependent ferroptosis has implications for a diverse range of pathological conditions. This review aims to present an updated definition of autophagy-dependent ferroptosis, discuss influential substrates and receptors, outline experimental methods, and propose guidelines for interpreting the results. Abbreviation : 3-MA:3-methyladenine; 4HNE: 4-hydroxynonenal; ACD: accidentalcell death; ADF: autophagy-dependentferroptosis; ARE: antioxidant response element; BH2:dihydrobiopterin; BH4: tetrahydrobiopterin; BMDMs: bonemarrow-derived macrophages; CMA: chaperone-mediated autophagy; CQ:chloroquine; DAMPs: danger/damage-associated molecular patterns; EMT,epithelial-mesenchymal transition; EPR: electronparamagnetic resonance; ER, endoplasmic reticulum; FRET: Försterresonance energy transfer; GFP: green fluorescent protein;GSH: glutathione;IF: immunofluorescence; IHC: immunohistochemistry; IOP, intraocularpressure; IRI: ischemia-reperfusion injury; LAA: linoleamide alkyne;MDA: malondialdehyde; PGSK: Phen Green™ SK;RCD: regulatedcell death; PUFAs: polyunsaturated fatty acids; RFP: red fluorescentprotein;ROS: reactive oxygen species; TBA: thiobarbituricacid; TBARS: thiobarbituric acid reactive substances; TEM:transmission electron microscopy.

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Progranulin released from microglial lysosomes reduces neuronal ferroptosis after cerebral ischemia in mice

Cited by 13 publications

References 63 publications

CCL5 mediated astrocyte-T cell interaction disrupts blood-brain barrier in mice after hemorrhagic stroke

CCL5 mediated astrocyte-T cell interaction disrupts blood-brain barrier in mice after hemorrhagic stroke

Identification of potential ferroptosis-associated biomarkers in rheumatoid arthritis

International consensus guidelines for the definition, detection, and interpretation of autophagy-dependent ferroptosis

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