Thioredoxin interacting protein, a key molecular switch between oxidative stress and sterile inflammation in cellular response

Abstract

Tissue and systemic inflammation have been the main culprit behind the cellular response to multiple insults and maintaining homeostasis. Obesity is an independent disease state that has been reported as a common risk factor for multiple metabolic and microvascular diseases including nonalcoholic fatty liver disease (NAFLD), retinopathy, critical limb ischemia, and impaired angiogenesis. Sterile inflammation driven by high-fat diet, increased formation of reactive oxygen species, alteration of intracellular calcium level and associated release of inflammatory mediators, are the main common underlying forces in the pathophysiology of NAFLD, ischemic retinopathy, stroke, and aging brain. This work aims to examine the contribution of the pro-oxidative and pro-inflammatory thioredoxin interacting protein (TXNIP) to the expression and activation of NLRP3-inflammasome resulting in initiation or exacerbation of sterile inflammation in these disease states. Finally, the potential for TXNIP as a therapeutic target and whether TXNIP expression can be modulated using natural antioxidants or repurposing other drugs will be discussed.

Keywords: Thioredoxin interacting protein; NOD-like receptor pyrin domain containing 3; Inflammasome; Interleukin 1b; Inflammation; Obesity; High-fat diet; Ischemia; Reperfusion; Oxidative stress

Core Tip: Inflammation has been postulated as the central pathway involved in maintaining homeostasis and in cellular response to insults. High fat diet-induced inflammasome activation have been reported to predispose microvascular diseases including retinopathy, and nonalcoholic fatty liver disease. Inflammation can alter vascular recovery in response to ischemic insult including ischemic retinopathy, stroke and critical limb ischemia. Thioredoxin interacting protein (TXNIP) is required for the activation but not necessarily for expression of NOD-like receptor pyrin domain containing 3-inflammasome resulting in initiation or exacerbation of the disease state. A list of natural antioxidants or repurposed drugs is included to modulate TXNIP expression.