Deletion of Thioredoxin-Interacting Protein (TXNIP) Abrogates High Fat Diet-induced Retinal Leukostasis, Barrier Dysfunction and Microvascular Degeneration in a Mouse Obesity Model.

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-1b, 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.
Authors	Islam N Mohamed, Nader Sheibani, Azza B El-Remessy
Journal	International journal of molecular sciences (Int J Mol Sci) Vol. 21 Issue 11 (Jun 01 2020) ISSN: 1422-0067 [Electronic] Switzerland
PMID	32492941 (Publication Type: Journal Article)
Chemical References	Carrier Proteins Cell Adhesion Molecules IL1B protein, mouse Inflammasomes Interleukin-1beta NLR Family, Pyrin Domain-Containing 3 Protein Nlrp3 protein, mouse TXNIP protein, human Txnip protein, mouse Thioredoxins Casp1 protein, mouse Caspase 1
Topics	Animals Blood-Retinal Barrier (pathology) Capillary Permeability Carrier Proteins (genetics) Caspase 1 (metabolism) Cell Adhesion Molecules Coculture Techniques Diet, High-Fat Disease Models, Animal Endothelial Cells (metabolism) Female Gene Deletion Humans Inflammasomes (metabolism) Inflammation Insulin Resistance Interleukin-1beta (metabolism) Leukostasis (pathology) Male Mice Mice, Inbred C57BL Mice, Knockout NLR Family, Pyrin Domain-Containing 3 Protein (metabolism) Obesity (metabolism) Retina (pathology) Thioredoxins (genetics)

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