Hyperlipidemia induces proinflammatory responses by activating STING pathway through IRE1α-XBP1 in retinal endothelial cells

Wen, Zheyao; He, Xianghui; Wang, Jin; Wang, Heting; Li, Ting; Wen, Siying; Ren, Zhitao; Cai, Nan; Yang, Jun; Li, Mei; Ai, Heying; Lu, Yan; Zhu, Yanhua; Shi, Guojun; Chen, Yanming

doi:10.1016/j.jnutbio.2022.109213

Cited by 9 publications

(10 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, hyperlipidaemia has also been reported to activate the STING pathway in endothelial cells in metabolic diseases. In retinal endothelial cells in diabetic retinopathy, hyperlipidaemia induces proinflammatory responses by activating the STING pathway via IRE1α-XBP1 [ 24 ]. Free fatty acids trigger endothelial inflammation through the STING–IRF3 axis in adipose tissue in diet-induced obesity in vivo [ 18 ] and inhibit endothelial angiogenesis through cGAS-STING-IRF3 signalling in vitro [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

Hyperglycemia-induced STING signaling activation leads to aortic endothelial injury in diabetes

An,

Geng,

Wang

et al. 2023

Cell Commun Signal

View full text Add to dashboard Cite

Hyperglycaemia-induced endothelial dysfunction is a key factor in the pathogenesis of diabetic microangiopathy and macroangiopathy. STING, which is a newly discovered regulator of innate immunity, has also been reported to play an important role in various metabolic diseases. However, the role of STING in diabetes-induced endothelial cell dysfunction is unknown. In this study, we established a diabetic macroangiopathy mouse model by streptozotocin (STZ) injection combined with high-fat diet (HFD) feeding and a glucotoxicity cell model in high glucose (HG)-treated rat aortic endothelial cells (RAECs). We found that STING expression was specifically increased in the endothelial cells of diabetic arteries, as well as in HG-treated RAECs. Moreover, genetic deletion of STING significantly ameliorated diabetes-induced endothelial cell dysfunction and apoptosis in vivo. Likewise, STING inhibition by C-176 reversed HG-induced migration dysfunction and apoptosis in RAECs, whereas STING activation by DMXAA resulted in migration dysfunction and apoptosis. Mechanistically, hyperglycaemia-induced oxidative stress promoted endothelial mitochondrial dysfunction and mtDNA release, which subsequently activated the cGAS-STING system and the cGAS-STING-dependent IRF3/NF-kB pathway, ultimately resulting in inflammation and apoptosis. In conclusion, our study identified a novel role of STING in diabetes-induced aortic endothelial cell injury and suggested that STING inhibition was a potential new therapeutic strategy for the treatment of diabetic macroangiopathy.

show abstract

Section: Discussionmentioning

confidence: 99%

Hyperglycemia-induced STING signaling activation leads to aortic endothelial injury in diabetes

An,

Geng,

Wang

et al. 2023

Cell Commun Signal

View full text Add to dashboard Cite

show abstract

“…[68] And penicillamine, another copper chelator, are shown to rescue retinal pigment epithelial cells by alleviating mi-tochondria dysfunction, ER stress and inflammation, [69] which are often found in diabetic epithelial cells. [70][71][72]…”

Section: Gdm Patients 8169mentioning

confidence: 99%

Copper and Diabetes: Current Research and Prospect

Chang,

2023

Molecular Nutrition Food Res

View full text Add to dashboard Cite

Copper is an essential trace metal for normal cellular functions; a lack of copper is reported to impair the function of important copper‐binding enzymes, while excess copper could lead to cell death. Numerous studies have shown an association between dietary copper consumption or plasma copper levels and the incidence of diabetes/diabetes complications. And experimental studies have revealed multiple signaling pathways that are triggered by copper shortages or copper overload in diabetic conditions. Moreover, studies show that treated with copper chelators improve vascular function, maintain copper homeostasis, inhibit cuproptosis, and reduce cell toxicity, thereby alleviating diabetic neuropathy, retinopathy, nephropathy, and cardiomyopathy. However, the mechanisms reported in these studies are inconsistent or even contradictory. This review summarizes the precise and tight regulation of copper homeostasis processes, and discusses the latest progress in the association of diabetes and dietary copper/plasma copper. Further, the study pays close attention to the therapeutic potential of copper chelators and copper in diabetes and its complications, and hopes to provide new insight for the treatment of diabetes.

show abstract

“…This interaction prompts the activation of pro-IL-1β and pro-caspase-1, key elements of the pro-inflammatory response ( 76 ). Interestingly, the retinal vasculature in mice displays significant expression of the stimulator of interferon genes (STING) protein ( 86 ). Moreover, mtDNA has the capacity to activate cyclic GMP-AMP synthase (cGAS), which augments the signaling of STING and subsequently triggers the release of interferons.…”

Section: Iron Overload and Drmentioning

confidence: 99%

Spotlight on iron and ferroptosis: research progress in diabetic retinopathy

Ouyang,

Zhou,

Wang

2023

Front. Endocrinol.

View full text Add to dashboard Cite

Iron, as the most abundant metallic element within the human organism, is an indispensable ion for sustaining life and assumes a pivotal role in governing glucose and lipid metabolism, along with orchestrating inflammatory responses. The presence of diabetes mellitus (DM) can induce aberrant iron accumulation within the corporeal system. Consequentially, iron overload precipitates a sequence of important adversities, subsequently setting in motion a domino effect wherein ferroptosis emerges as the utmost pernicious outcome. Ferroptosis, an emerging variant of non-apoptotic regulated cell death, operates independently of caspases and GSDMD. It distinguishes itself from alternative forms of controlled cell death through distinctive morphological and biochemical attributes. Its principal hallmark resides in the pathological accrual of intracellular iron and the concomitant generation of iron-driven lipid peroxides. Diabetic retinopathy (DR), established as the predominant cause of adult blindness, wields profound influence over the well-being and psychosocial strain experienced by afflicted individuals. Presently, an abundance of research endeavors has ascertained the pervasive engagement of iron and ferroptosis in the microangiopathy inherent to DR. Evidently, judicious management of iron overload and ferroptosis in the early stages of DR bears the potential to considerably decelerate disease progression. Within this discourse, we undertake a comprehensive exploration of the regulatory mechanisms governing iron homeostasis and ferroptosis. Furthermore, we expound upon the subsequent detriments induced by their dysregulation. Concurrently, we elucidate the intricate interplay linking iron overload, ferroptosis, and DR. Delving deeper, we engage in a comprehensive deliberation regarding strategies to modulate their influence, thereby effecting prospective interventions in the trajectory of DR’s advancement or employing them as therapeutic modalities.

show abstract

Hyperlipidemia induces proinflammatory responses by activating STING pathway through IRE1α-XBP1 in retinal endothelial cells

Cited by 9 publications

References 53 publications

Hyperglycemia-induced STING signaling activation leads to aortic endothelial injury in diabetes

Hyperglycemia-induced STING signaling activation leads to aortic endothelial injury in diabetes

Copper and Diabetes: Current Research and Prospect

Spotlight on iron and ferroptosis: research progress in diabetic retinopathy

Contact Info

Product

Resources

About