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

Diabetic retinopathy (DR) is one of the most prevalent microvascular complications caused by diabetes mellitus. Previous studies demonstrate that microvascular endothelial inflammation caused by chronic hyperglycemia and hyperlipidemia plays a key role in the pathogenesis of DR. However, the detailed mechanisms on how endothelial inflammation contributes to DR are not fully understood. The STING pathway is an important innate immune signaling pathway. Although STING has been implicated in multiple autoimmune and metabolic diseases, it is not clear whether STING is involved in the pathogenesis of DR. Thus, re-analysis of the public single cell RNA sequencing (sc-RNAseq) data demonstrated that STING was highly expressed in mouse retinal vessels. Moreover, our results demonstrated that STING and p-TBK1 protein levels in retinal endothelial cells are significantly increased in mice fed with high fat diet compared with chow diet. In vitro , palmitic acid treatment on HRVECs induced mitochondrial DNA leakage into the cytosol, and augmented p-TBK1 protein and IFN-beta mRNA levels. As STING is localized to the ER, we analyzed the relation between STING activation and ER stress. In HRVECs, STING pathway was shown to be activated under chemical-induced ER stress, but attenuated when IRE1 alpha was abolished by genetic deletion or pharmacological inhibition. Taken together, our findings revealed that STING signaling plays an important role in mediating lipotoxicity-induced endothelial inflammatory and injury, and IRE1 alpha-XBP1 signaling potentiated STING signaling. Thus, targeting the IRE1 alpha or STING pathways to alleviate endothelial inflammation provides candidate therapeutic target for treating DR as well as other microvascular complications.(c) 2022 Elsevier Inc. All rights reserved.

Automated summary

Diabetic retinopathy (DR) is a common microvascular complication caused by diabetes mellitus. Chronic hyperglycemia and hyperlipidemia lead to endothelial inflammation, but the detailed mechanisms are not fully understood. This study analyzed single cell RNA sequencing data and found that the STING pathway is highly expressed in mouse retinal vessels. Further experiments showed that STING and p-TBK1 protein levels were increased in retinal endothelial cells of mice fed with a high fat diet. In vitro experiments demonstrated that STING pathway activation was induced by ER stress and potentiated by IRE1 alpha-XBP1 signaling. These findings suggest that targeting the STING pathway may provide a therapeutic approach for treating DR and other microvascular complications.