Integrated multi-omics reveals the activated retinal microglia with intracellular metabolic reprogramming contributes to inflammation in STZ-induced early diabetic retinopathy

Abstract

Diabetic retinopathy (DR) is the leading cause of visual impairment and blindness among working-age people. Inflammation is recognized as a critical driver of the DR process. However, the main retina-specific cell type producing pro-inflammatory cytokines and its mechanism underlying DR are still unclear. Here, we used single-cell sequencing to identify microglia with metabolic pathway alterations that were the main source of IL-1β in STZ-induced DR mice. To profile the full extent of local metabolic shifts in activated microglia and to reveal the metabolic microenvironment contributing to immune mechanisms, we performed integrated metabolomics, lipidomics, and RNA profiling analyses in microglia cell line samples representative of the DR microenvironment. The results showed that activated microglia with IL-1β increase exhibited a metabolic bias favoring glycolysis, purine metabolism, and triacylglycerol synthesis, but less Tricarboxylic acid (TCA). In addition, some of these especially glycolysis was necessary to facilitate their pro-inflammation. These findings suggest that activated microglia with intracellular metabolic reprogramming in retina may contribute to pro-inflammation in the early DR.

More than meets the eye: The role of microglia in healthy and diseased retina

“…Per se, ischemia and hyperglycemia are potent activators of microglia, as indicated in several in vitro studies (300) and further observed in mice (88, [301][302][303] and rats in which type 1 diabetes was induced with streptozotocin (STZ) (89,(304)(305)(306)(307)(308) as well as in human patients (294,309,310). As described for other pathologies, activation includes events like proliferation, retraction of processes and acquisition of an amoeboid shape.…”

Metabolomics of various samples advancing biomarker discovery and pathogenesis elucidation for diabetic retinopathy

“…With BV2 murine microglia representative of the DR microenvironment, Lv et al conducted integrated metabolomics, lipidomics, and RNA profiling analyses to profile the full extent of local metabolic changes and explore the effect of the metabolic microenvironment on immune mechanisms. For the metabolomic part, 78 differential metabolites were identified, which were mainly significantly enriched in purine metabolism, glycolysis, and other metabolic pathways (72). To explore the effect of sodium-glucose cotransporter-2 inhibitors dapagliflozin on apoptosis of human retinal microvascular endothelial cells, Hu et al performed metabolomic analysis to find 38 significantly different expressed metabolites.…”

A Novel Ultrafiltrate Extract of Propolis Exerts Anti‐inflammatory Activity through Metabolic Rewiring

“…Moreover, the level of 2‐ketobutyric acid is related to TCA cycle function, which will be changed in a state of inflammation [15] . So do the glucose metabolism under different inflammatory conditions [16] …”

“…[15] So do the glucose metabolism under different inflammatory conditions. [16] Similarly, the alteration of amino acid metabolism is considered as a metabolic characteristic of sepsis. [17] IL-1β is a key inflammatory cytokine in inflammatory response, which promotes further glutamate release.…”