Abstract
We have shown that a high fat diet (HFD) induces the activation of retinal NOD-like receptor protein (NLRP3)-inflammasome that is associated with enhanced expression and interaction with thioredoxin-interacting protein (TXNIP). Here, the specific contribution of TXNIP and the impact of HFD on retinal leukostasis, barrier dysfunction and microvascular degeneration were investigated. Wild-type (WT) and TXNIP knockout (TKO) mice were fed with normal diet or 60% HFD for 8–18 weeks. TXNIP was overexpressed or silenced in human retinal endothelial cells (REC). At 8 weeks, HFD significantly induced retinal leukostasis and breakdown of the blood–retina barrier in WT mice, but not in TKO mice. In parallel, HFD also induced retinal expression of adhesion molecules and cleaved IL-1β in WT mice, which were also abrogated in TKO mice. In culture, TXNIP overexpression induced NLRP3, IL-1β, and adhesion molecules expression, while TXNIP silencing inhibited them. Blocking the IL-1β receptor significantly suppressed TXNIP-induced expression of NLRP3-inflammasome and adhesion molecules in HREC. Ex-vivo assay showed that leukocytes isolated from WT-HFD, but not from TKO-HFD, induced leukostasis and cell death. At 18 weeks, HFD triggered development of degenerated (acellular) capillaries and decreased branching density in WT but not in TKO mice. Together, HFD-induced obesity triggered early retinal leukostasis and microvascular dysfunction at least in part via TXNIP-NLRP3-inflammasome activation.
Highlights
Retinal inflammation and leukostasis, defined by abnormal adhesion between activated leukocytes and microvasculature, are well-defined milestones in the development of diabetic retinopathy (DR)
Six-week-old age and gender matched C57Bl/6J wild-type mice (WT) and thioredoxin-interacting protein (TXNIP) knockout (TKO) mice were inbred at the facility and randomized for feeding with either standard chow or high fat diet (WT-HFD and TKO-HFD groups) for 8 weeks or 18 weeks
Our results indicated that HFD induced NLRP3-inflammasome activation, which was associated with parallel increases in retinal vascular cell adhesion molecules, leukostasis and blood retinal barrier (BRB) breakdown after 8 weeks in WT-HFD compared with ND-controls (Figures 2–4)
Summary
Retinal inflammation and leukostasis, defined by abnormal adhesion between activated leukocytes and microvasculature, are well-defined milestones in the development of diabetic retinopathy (DR) (reviewed in [1,2]). Leukocytes can uniquely target injured tissues, adhere to the vasculature, and locally secrete pro-inflammatory mediators. These events are paralleled by increased expression of intracellular adhesion molecules, which accelerate the onset of leukostasis [1]. A growing body of evidence has recognized sterile inflammation manifested by increased retinal caspase-1 activation and IL-1β levels to have a causative role in initiating and sustaining retinal microvascular dysfunction and degeneration [5,6,7]. The majority of the evidence linking inflammatory processes to development of DR has extensively focused on insulin-deficient rather than insulin-resistant rodent models
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