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

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.     

Higher hydroxyurea adherence among young adults with sickle cell disease compared to children and adolescents

BackgroundSickle cell disease (SCD) results in severe complications, such as anaemia and pain episodes. Hydroxyurea (HU) is efficacious in SCD, yet adherence remains low.ObjectiveTo assess the relationship of HU adherence to health care utilization and patients’ characteristics.MethodsThis is a 5-year retrospective chart review. Patients’ demographics and medical history were collected from the electronic medical record (EMR). HU adherence was evaluated using foetal haemoglobin “HbF%”, mean corpuscular volume “MCV”, and absolute neutrophil count “ANC”. Age groups included children (<12 years), adolescents (12–17 years), and young adults (≥18 years).ResultsA total of 113 SCD patients on HU were included (median age 14 years, IQR 10–20; 50% female; 88% HbSS). Young adults had significantly higher HU adherence compared to adolescents and children, including higher median HbF% (24.2 vs. 12.4 vs. 8.6, p = .003), MCV (fl) (106.4 vs. 96.2 vs. 95.4, p = .01) and lower ANC (10³/ml) (3.25 vs. 4.9 vs. 4.2, p = .01), respectively. Patients with chronic pain had lower HU adherence (HbF% 15.3 vs. 10.7, p = .04; ANC 3.6 vs. 6.3, p = .002; MCV 102.3 vs. 93.1, p = .1). Patients with higher HbF or MCV and lower ANC had significantly less frequent emergency room visits (r_s=–0.26, p = .01; r_s=–0.23, p = .01; r_s=0.24, p = .01) and hospitalizations (r_s=–0.27, p = .01; r_s=–0.31, p = .01; r_s=0.21, p = .02) as well as shorter length of stays (r_s=–0.27, p = .0045; r_s=–.34, p = 0.004; r_s=0.23, p = .02), respectively. Similar trends in HU adherence and health care utilization were seen in subgroup analysis of only HbSS patients. There was no significant association of HU adherence to patients’ sex, socio-economic status, distance from hospital, and HU duration.ConclusionsYoung adults with SCD had significantly higher HU adherence compared to children and adolescents. Patients with lower HU adherence and/or chronic pain had increased health care utilization. Future studies examining barriers to adherence and evaluating interventions to optimize HU adherence in SCD are warranted.

KEY MESSAGES

1. Young adults with SCD had significantly higher HU adherence, as reflected in their laboratory markers, compared to children and adolescents.
2. Patients with higher HU adherence and/or those without chronic pain had lower or less frequent health care utilization.
3. No significant association of HU adherence to patients’ sex, socio-economic status and distance from hospital.

     

The impact of sarcopenia on the outcome of patients with cirrhosis with and without hepatocellular carcinoma who undergo liver transplantation

Background: The impact of sarcopenia on the outcome of patients with cirrhosis who undergo liver transplantation (LT) has been analysed in heterogeneous cohorts...     

Narrowed coraco-humeral distance on MRI: Association with subscapularis tendon tear

Purpose

To highlight the relationship between coraco-humeral distance and subscapularis tendon tear.