STAT3 activation in microglia increases pericyte apoptosis in diabetic retinas through TNF-ɑ/AKT/p70S6 kinase signaling

Yun, Jang-Hyuk; Lee, Da-Hye; Jeong, Hyunjo; Kim, Seung‐Hoon; Ye, Sang‐Kyu; Cho, Chung–Hyun

doi:10.1016/j.bbrc.2022.05.004

Cited by 19 publications

(14 citation statements)

References 25 publications

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“…Pdgfrb is one of the receptors for PDGF that regulates vasculogenesis and fibroblast proliferation, and it is implicated in the pathogenesis of ROP 59 . Stat3 regulates cytokine signaling in the immune system, NF-κB transcription factor activity, and endothelial cell proliferation, and its activation in microglia increases pericyte apoptosis 60 . These data further highlight the importance of GSDMD-KO in protecting against hyperoxia-induced inflammation, abnormal vasculogenesis, and tissue remodeling in the retinas.…”

Section: Discussionmentioning

confidence: 99%

GSDMD deficiency ameliorates hyperoxia-induced BPD and ROP in neonatal mice

Sonny

Yuan

Chen

et al. 2023

Sci Rep

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Bronchopulmonary dysplasia (BPD) and retinopathy of prematurity (ROP) are among the most common morbidities affecting extremely premature infants who receive oxygen therapy. Many clinical studies indicate that BPD is associated with advanced ROP. However, the mechanistic link between hyperoxia, BPD, and ROP remains to be explored. Gasdermin D (GSDMD) is a key executor of inflammasome-induced pyroptosis and inflammation. Inhibition of GSDMD has been shown to attenuate hyperoxia-induced BPD and brain injury in neonatal mice. The objective of this study was to further define the mechanistic roles of GSDMD in the pathogenesis of hyperoxia-induced BPD and ROP in mouse models. Here we show that global GSDMD knockout (GSDMD-KO) protects against hyperoxia-induced BPD by reducing macrophage infiltration, improving alveolarization and vascular development, and decreasing cell death. In addition, GSDMD deficiency prevented hyperoxia-induced ROP by reducing vasoobliteration and neovascularization, improving thinning of multiple retinal tissue layers, and decreasing microglial activation. RNA sequencing analyses of lungs and retinas showed that similar genes, including those from inflammatory, cell death, tissue remodeling, and tissue and vascular developmental signaling pathways, were induced by hyperoxia and impacted by GSDMD-KO in both models. These data highlight the importance of GSDMD in the pathogenesis of BPD and ROP and suggest that targeting GSDMD may be beneficial in preventing and treating BPD and ROP in premature infants.

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Section: Discussionmentioning

confidence: 99%

GSDMD deficiency ameliorates hyperoxia-induced BPD and ROP in neonatal mice

Sonny

Yuan

Chen

et al. 2023

Sci Rep

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“…These observations indicate a specific protective role of microglial PPARα in maintaining integrity and function of the neurovascular unit. The relationship between microglial activation and pericyte apoptosis has been reported previously [ 62 , 63 , 64 ]. Gardiner et al identified that in retinas from diabetic patients, juxtavascular microglia penetrate the basement membrane to scavenge and phagocytose pericytes [ 65 ].…”

Section: Discussionmentioning

confidence: 53%

The Protective Role of Microglial PPARα in Diabetic Retinal Neurodegeneration and Neurovascular Dysfunction

Yuan

Dong

Pearsall

et al. 2022

Cells

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Microglial activation and subsequent pathological neuroinflammation contribute to diabetic retinopathy (DR). However, the underlying mechanisms of microgliosis, and means to effectively suppress pathological microgliosis, remain incompletely understood. Peroxisome proliferator-activated receptor alpha (PPARα) is a transcription factor that regulates lipid metabolism. The present study aimed to determine if PPARα affects pathological microgliosis in DR. In global Pparα mice, retinal microglia exhibited decreased structural complexity and enlarged cell bodies, suggesting microglial activation. Microglia-specific conditional Pparα−/− (PCKO) mice showed decreased retinal thickness as revealed by optical coherence tomography. Under streptozotocin (STZ)-induced diabetes, diabetic PCKO mice exhibited decreased electroretinography response, while diabetes-induced retinal dysfunction was alleviated in diabetic microglia-specific Pparα-transgenic (PCTG) mice. Additionally, diabetes-induced retinal pericyte loss was exacerbated in diabetic PCKO mice and alleviated in diabetic PCTG mice. In cultured microglial cells with the diabetic stressor 4-HNE, metabolic flux analysis demonstrated that Pparα ablation caused a metabolic shift from oxidative phosphorylation to glycolysis. Pparα deficiency also increased microglial STING and TNF-α expression. Taken together, these findings revealed a critical role for PPARα in pathological microgliosis, neurodegeneration, and vascular damage in DR, providing insight into the underlying molecular mechanisms of microgliosis in this context and suggesting microglial PPARα as a potential therapeutic target.

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“…STAT3 activation in microglia played an important role in pericyte apoptosis in DR through increased TNF-α expression. Another studies have found that [41] melatonin deactivated microglia via inhibition of PI3K/Akt/STAT3/NF-κB signaling pathways, thus maintaining the integrity of iBRB. This suggests that STAT3 may be involved in BRB damage.…”

Section: Construction Of Ppi Network and Molecular Dockingmentioning

confidence: 97%

“…Latest research found that [41] STAT3 activation increased in DR because STAT3 activation is associated with in ammation. STAT3 activation in microglia played an important role in pericyte apoptosis in DR through increased TNF-α expression.…”

Section: Construction Of Ppi Network and Molecular Dockingmentioning

confidence: 99%

Protective mechanism of Scutellarin against pyroptosis network in diabetic retinopathy

Guo

et al. 2022

Preprint

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Objective To investigate the regulation and network mechanism of SCU on pyrodeath gene in diabetic retinopathy. Methods The animal model of DM was established and the retinopathy was observed by HE staining, Ni staining and immunofluorescence staining. The retinopathy of SCU group was significantly improved. DR gene, cell pyrophoric gene and astragaloside IV gene were queried, Venny intersection was performed, GO and KEGG analysis was performed, PPI protein interaction was performed, and Hub gene was screened for molecular docking verification. Results 4084 genes related to DR were screened from GeneCards and OMIM databases. Using GeneCards, TCMSP and Swiss Target Prediction databases, 120 SCU therapeutic targets were obtained. Using GenenCards database, 357 targets related to coke decay were retrieved. Drug, disease and phenotypic targets were analyzed online using the Draw Venn Diagram website, and 12 cross targets were obtained. Through GO function and KEGG pathway enrichment analysis of common targets, 659 BP related items, 7 CC related items, 30 MF related items, and 70 signal pathways were screened out. Eleven proteins were screened to interact with the cross-target PPI network, and 11 proteins were subsequently docked with the SCU. The results show that SCU has good binding activity to the core. Conclusion SCU can regulate the death reaction of DR coke through multi-target and multi-pathway, and reveal its possible mechanism.

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STAT3 activation in microglia increases pericyte apoptosis in diabetic retinas through TNF-ɑ/AKT/p70S6 kinase signaling

Cited by 19 publications

References 25 publications

GSDMD deficiency ameliorates hyperoxia-induced BPD and ROP in neonatal mice

GSDMD deficiency ameliorates hyperoxia-induced BPD and ROP in neonatal mice

The Protective Role of Microglial PPARα in Diabetic Retinal Neurodegeneration and Neurovascular Dysfunction

Protective mechanism of Scutellarin against pyroptosis network in diabetic retinopathy

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