α-Synuclein Induces Neuroinflammation Injury through the IL6ST-AS/STAT3/HIF-1α Axis

Lin, Danyu; Zhang, Han; Zhang, Jieli; Huang, Kaixun; Chen, Ying; Jing, Xin; Tao, Enxiang

doi:10.3390/ijms24021436

Cited by 10 publications

(4 citation statements)

References 31 publications

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“…While proinflammatory cytokines could be derived from other cell types, such as blood‐derived macrophages that infiltrated the retina, our results highlight the enhanced responses of highly myopic eyes to proinflammatory environment. Notably, the STAT3 signaling pathway was activated in highly myopic microglia characterized by elevated p‐STAT3 expression, exhibiting an aging or neuroinflammatory profile 46,47 . Because this activation might be a response to the pathological environment in highly myopic retinas or an amplifier to exacerbate myopia progression via regulating myopia‐related genes, further studies are needed to dissect the causal relationship between these two events.…”

Section: Discussionmentioning

confidence: 99%

“…Notably, the STAT3 signaling pathway was activated in highly myopic microglia characterized by elevated p-STAT3 expression, exhibiting an aging or neuroinflammatory profile. 46,47 Because this activation might be a response to the pathological environment in highly myopic retinas or an amplifier to exacerbate myopia progression via regulating myopia-related genes, further studies are needed to dissect the causal relationship between these two events.…”

Section: Discussionmentioning

confidence: 99%

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Single‐cell RNA sequencing of retina revealed novel transcriptional landscape in high myopia and underlying cell‐type‐specific mechanisms

Yao,

Chen,

et al. 2023

MedComm

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High myopia is a leading cause of blindness worldwide with increasing prevalence. Retina percepts visual information and triggers myopia development, but the underlying etiology is not fully understood because of cellular heterogeneity. In this study, single‐cell RNA sequencing analysis was performed on retinas of mouse highly myopic and control eyes to dissect the involvement of each cell type during high myopia progression. For highly myopic photoreceptors, Hk2 inhibition underlying metabolic remodeling from aerobic glycolysis toward oxidative phosphorylation and excessive oxidative stress was identified. Importantly, a novel Apoe+ rod subpopulation was specifically identified in highly myopic retina. In retinal neurons of highly myopic eyes, neurodegeneration was generally discovered, and the imbalanced ON/OFF signaling driven by cone‐bipolar cells and the downregulated dopamine receptors in amacrine cells were among the most predominant findings, indicating the aberrant light processing in highly myopic eyes. Besides, microglia exhibited elevated expression of cytokines and TGF‐β receptors, suggesting enhanced responses to inflammation and the growth‐promoting states involved in high myopia progression. Furthermore, cell–cell communication network revealed attenuated neuronal interactions and increased glial/vascular interactions in highly myopic retinas. In conclusion, this study outlines the transcriptional landscape of highly myopic retina, providing novel insights into high myopia development and prevention.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Single‐cell RNA sequencing of retina revealed novel transcriptional landscape in high myopia and underlying cell‐type‐specific mechanisms

Yao,

Chen,

et al. 2023

MedComm

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“…[67,92,115] Consequently, this process induces dysfunction and death in dopaminergic neurons, leading to the depletion of dopamine, a pivotal factor in the manifestation of motor dysfunction observed in PD. Simultaneously, the aberrant aggregation of α-Syn also triggers neuroinflammation and mitochondrial damage, [116,117] indicating an interplay of various pathological manifestations in PD, forming a vicious cycle. Notably, aggregated α-Syn in the brain can propagate in a prion-like manner within the body, emerging as a crucial factor in the pathological progression of PD.…”

Section: Scfas and Aberrant Aggregation Of α-Synuclein (α-Syn)mentioning

confidence: 99%

Interplay of human gastrointestinal microbiota metabolites: Short-chain fatty acids and their correlation with Parkinson’s disease

Liu,

Chen,

2024

Medicine

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Short-chain fatty acids (SCFAs) are, the metabolic byproducts of intestinal microbiota that, are generated through anaerobic fermentation of undigested dietary fibers. SCFAs play a pivotal role in numerous physiological functions within the human body, including maintaining intestinal mucosal health, modulating immune functions, and regulating energy metabolism. In recent years, extensive research evidence has indicated that SCFAs are significantly involved in the onset and progression of Parkinson disease (PD). However, the precise mechanisms remain elusive. This review comprehensively summarizes the progress in understanding how SCFAs impact PD pathogenesis and the underlying mechanisms. Primarily, we delve into the synthesis, metabolism, and signal transduction of SCFAs within the human body. Subsequently, an analysis of SCFA levels in patients with PD is presented. Furthermore, we expound upon the mechanisms through which SCFAs induce inflammatory responses, oxidative stress, abnormal aggregation of alpha-synuclein, and the intricacies of the gut-brain axis. Finally, we provide a critical analysis and explore the potential therapeutic role of SCFAs as promising targets for treating PD.

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“…We previously reported that the overexpression of IL6ST-AS induced by exogenous α-syn could inhibit the expression of IL6ST and the activation of JAK2/STAT3/HIF-1α pathway in HMC3 cells 11 . The Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway is the major signaling mechanism for a broad array of cytokines and growth factors, widely participating in biological processes such as immunomodulatory cell proliferation, differentiation, and apoptosis 12 .…”

Section: Introductionmentioning

confidence: 96%

STAT3-mediated ferroptosis is involved in α-synuclein pathology

Zhang¹,

Jing

Zhang³

et al. 2023

Preprint

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Background Oligomeric α-synuclein (α-syn) can activate microglia to drive the early stages of Parkinson's disease (PD) pathogenesis. Our previous studies have found a significant expression difference between the lncRNA IL6ST-AS and its antisense RNA IL6ST in the cerebrospinal fluid of PD patients. Furthermore, in α-syn-induced HMC3 cells, a decline in IL6ST and its downstream target JAK2/STAT3 were also observed. Accumulating investigations have illustrated that STAT3 regulates the expression of ferroptosis-related genes and further influences the proliferation of cells.Methods The role and mechanisms of IL6ST/JAK2/STAT3 axis in α-syn induced HMC3 cells and PD mouse models were explored by Western blot or immunohistochemistry. Transcriptome sequencing of HMC3 cells exposed to α-syn oligomers and PD mouse models were performed. The STAT3 activator and the STAT3 inhibitor were used to regulate the expression of STAT3. qPCR was used to detect the expression of ferroptosis regulation genes (FRG) in HMC3 cells induced by α-syn or STAT3 inhibitor. ROS, lipid peroxidation and iron levels were measured by flow cytometry.Results We found that α-syn could impair cell activity and stalely inhibit the IL6ST/ STAT3/HIF-1α pathway in α-syn-induced HMC3 cells. Besides, we performed transcriptomic analysis for α-syn-induced HMC3 cells and in α-syn-induced PD mouse models and GSEA indicated an association with ferroptosis. The reduction in P-STAT3 resulted in the lower expression of HIF-1α and the transcriptional activation of ferroptosis positive regulation (FPR) genes. P-STAT3 mediated ferroptotic cell death in α-syn-induced HMC3 cells by modulating lipid peroxidation and iron metabolism levels. An in vivo study revealed that the IL6ST/JAK2/STAT3/HIF-1α pathway was upregulated in PD mouse models.Conclusions STAT3 was an important factor that regulates ferroptosis in α-syn pathology via the JAK2/STAT3/HIF-1α axis. Our research illustrated the relationship of the JAK2/STAT3/HIF-1α axis and ferroptosis in the pathological process of α-syn both in vitro and in vivo, providing new topics of interest regarding the inflammation damage hypothesis and pathogenesis in PD.

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α-Synuclein Induces Neuroinflammation Injury through the IL6ST-AS/STAT3/HIF-1α Axis

Cited by 10 publications

References 31 publications

Single‐cell RNA sequencing of retina revealed novel transcriptional landscape in high myopia and underlying cell‐type‐specific mechanisms

Single‐cell RNA sequencing of retina revealed novel transcriptional landscape in high myopia and underlying cell‐type‐specific mechanisms

Interplay of human gastrointestinal microbiota metabolites: Short-chain fatty acids and their correlation with Parkinson’s disease

STAT3-mediated ferroptosis is involved in α-synuclein pathology

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