Thioredoxin-interacting protein is required for endothelial NLRP3 inflammasome activation and cell death in a rat model of high-fat diet

Abstract

Aims/hypothesis Obesity and hypertension, known pro-inflammatory states, are identified determinants for increased retinal microvascular abnormalities. However, the molecular link between inflammation and microvascular degeneration remains elusive. Thioredoxin-interacting protein (TXNIP) is recognised as an activator of the NOD-like receptor pyrin domain containing-3 (NLRP3) inflammasome. This study aims to examine TXNIP expression and elucidate its role in endothelial inflammasome activation and retinal lesions. Methods Spontaneously hypertensive (SHR) and control Wistar (W) rats were compared with groups fed a high-fat diet (HFD) (W+F and SHR+F) for 8–10 weeks. Results Compared with W controls, HFD alone or in combination with hypertension significantly induced formation of acellular capillaries, a hallmark of retinal ischaemic lesions. These effects were accompanied by significant increases in lipid peroxidation, nitrotyrosine and expression of TXNIP, nuclear factor κB, TNF-α and IL-1β. HFD significantly increased interaction of TXNIP–NLRP3 and expression of cleaved caspase-1 and cleaved IL-1β. Immunolocalisation studies identified TXNIP expression within astrocytes and Müller cells surrounding retinal endothelial cells. To model HFD in vitro, human retinal endothelial (HRE) cells were stimulated with 400 μmol/l palmitate coupled to BSA (Pal-BSA). Pal-BSA triggered expression of TXNIP and its interaction with NLRP3, resulting in activation of caspase-1 and IL-1β in HRE cells. Silencing Txnip expression in HRE cells abolished Pal-BSA-mediated cleaved IL-1β release into medium and cell death, evident by decreases in cleaved caspase-3 expression and the proportion of live to dead cells. Conclusions/interpretation These findings provide the first evidence for enhanced TXNIP expression in hypertension and HFD-induced retinal oxidative/inflammatory response and suggest that TXNIP is required for HFD-mediated activation of the NLRP3 inflammasome and the release of IL-1β in endothelial cells.

NF-κB Blockade in Hypothalamic Paraventricular Nucleus Inhibits High-Salt-Induced Hypertension Through NLRP3 and Caspase-1

“…It is consisted of studies from others and our previous work [7,30,31]. The maturation of IL-1b is dependent on NLRP3 inflammasome assembling and the following activation [9,32,33]. However, little attention has been directed toward identifying the role of NLRP3 inflammasome in the PVN of saltsensitive hypertensive rats.…”

“…The maturation of IL-1b is dependent on NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome assembling and the following activation [9], but at present, there are no reports on regulation of NLRP3 within the PVN.…”

Coronary Endothelial Dysfunction Induced by Nucleotide Oligomerization Domain-Like Receptor Protein with Pyrin Domain Containing 3 Inflammasome Activation During Hypercholesterolemia: Beyond Inflammation

“…Activation of Nlrp3 can induce cell death via caspase-dependent mechanisms (27,34). Previous studies have shown that activation of Nlrp3 inflammasome has also been shown to induce cell death in human retinal ECs (28). Nlrp3 deficiency prevented caspase 3-mediated apoptosis by upregulating autophagy, specifically mitophagy in lungs and lung ECs during hyperoxia (56).…”

NLRP3 deficiency protects from type 1 diabetes through the regulation of chemotaxis into the pancreatic islets

“…It is known that the NLRP3 inflammasome plays a role in the development of insulin resistance and T2D (12)(13)(14)31). However, the role of the NLRP3 inflammasome in autoimmune T1D remained to be explored.…”