| First Author | Mohamed IN | Year | 2020 |
| Journal | Int J Mol Sci | Volume | 21 |
| Issue | 11 | PubMed ID | 32492941 |
| Mgi Jnum | J:305377 | Mgi Id | MGI:6706233 |
| Doi | 10.3390/ijms21113983 | Citation | Mohamed IN, et al. (2020) Deletion of Thioredoxin-Interacting Protein (TXNIP) Abrogates High Fat Diet-induced Retinal Leukostasis, Barrier Dysfunction and Microvascular Degeneration in a Mouse Obesity Model. Int J Mol Sci 21(11):3983 |
| abstractText | 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-1beta in WT mice, which were also abrogated in TKO mice. In culture, TXNIP overexpression induced NLRP3, IL-1b, and adhesion molecules expression, while TXNIP silencing inhibited them. Blocking the IL-1beta 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. |
