NLRP3 inflammasomes link inflammation and metabolic disease - PubMed (original) (raw)

Review

Dominic De Nardo et al. Trends Immunol. 2011 Aug.

Abstract

A strong link between inflammation and metabolism is becoming increasingly evident. A number of recent landmark studies have implicated the activation of the NLRP3 inflammasome, an interleukin-1β family cytokine-activating protein complex, in a variety of metabolic diseases including obesity, atherosclerosis and type 2 diabetes. Here, we review these new developments and discuss their implications for a better understanding of inflammation in metabolic disease, and the prospects of targeting the NLRP3 inflammasome for therapeutic intervention.

Copyright © 2011 Elsevier Ltd. All rights reserved.

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Figures

Figure 1

Figure 1. NLRP3 inflammasome activation in atherosclerosis

In order for NLRP3 inflammasome to be activated in atherosclerosis it must first be primed via recognition of modified LDL by TLRs and scavenger receptors on macrophages. This priming step allows upregulation of pro-IL-1β and NLRP3. Subsequently, modified LDL-induced cholesterol crystals that are phagocytosed by macrophages cause lysosomal rupture, allowing release of lysosomal proteases (cathepsins). Potentially in combination with ROS production, cathepsins mediate the activation of the NLRP3 inflammasome resulting in caspase-1 cleavage and the production of mature IL-1 cytokine. Mature IL-1 is then released from cells causing continued upregulation of inflammasome components as well as mediating an inflammatory response that results in an influx of immune cells and the progression of atherosclerotic plaque formation.

Figure 2

Figure 2. Obesity is a key facilitator of NLRP3 inflammasome induction in metabolic disease

Obesity often supplies the initial signals required to prime the NLRP3 inflammasome that can include modified LDL and free fatty acids. Many of the metabolic danger signals subsequently sensed by the NLRP3 inflammasome are also a direct/indirect result of obesity. Once the inflammasome has been engaged by a specific danger signal the resulting pro-inflammatory induced state often leads to progression of a particular metabolic disease.

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