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The role of Nrf2 in NLRP3 inflammasome activation

Cellular & Molecular Immunology volume 14, pages 1011–1012 (2017)Cite this article

The nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3 (NLRP3) inflammasome is one of the pattern recognition receptors for host defense against pathogen-associated molecular patterns and danger-associated molecular patterns. The NLRP3 inflammasome is a best characterized as a multiprotein complex composed of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) adaptor, and pro-caspase-1. The NLRP3 inflammasome is activated by select activators or pathogen stimuli, and a conformational change of inflammasome-forming NOD-like receptor (NLR) enables NLR binding to ASC via pyrin domains. The adaptor ASC then conjugates with pro-caspase-1 through a caspase recruitment domain. Significant action of the NLRP3 inflammasome provides a molecular modification of pro-caspase-1, cleaving it into caspase-1 and thereby mediating IL-1β maturation and secretion from its precursor pro-IL-1β.1 NLRP3 inflammasome activators include whole pathogens, pathogen-associated molecules, environmental insults, and endogenous danger signals. However, it has been well documented that the signals controlling NLRP3 inflammasome activation by these activators are intracellular reactive oxygen species (ROS) or mitochondrial ROS.1, 2 The redox homeostasis associated transcription factor, known as nuclear factor E2-related factor 2 (Nrf2), has been further studied for its potential role in NLRP3 inflammasome activation.

Several publications demonstrate that Nrf2-activating compounds, such as tertiary butylhydroquinone, sulforaphane, and xanthohumol, can suppress IL-1β secretion by up-regulating Nrf2-mediated NAD(P)H:quinone oxidoreductase 1 (NQO-1), heme oxygenase-1 (HO-1), and glutamate cysteine ligase expression.8, 9, 10 These antioxidant responses further scavenge ROS, resulting in maintenance of the thioredoxin/thioredoxin interaction protein system and down-regulation of ROS-priming NF-κB signaling. It seems that these Nrf2-activating compounds indirectly control IL-1β secretion because it is unclear whether cytosolic Nrf2 or its repressor Keap-1 directly changes the conformation of the NLRP3 inflammasome and interacts with one of the NLRP3 inflammasome components. In some cases, NLRP3 inflammasome activators, such as cholesterol, induce Nrf2-dependent genes, including peroxiredoxin-1, NQO-1 and HO-1,3 and MSU, which can trigger Nrf2 translocation into the nucleus with increasing mRNA levels of superoxide dismutase and HO-1.5 MSU-induced lysosomal disruption and p62/SQSTM1 accumulation are indicated as the major causes of Nrf2 activation.5 Furthermore, IL-1β secretion was also suppressed via silencing of HO-1 or by using HO-1 inhibitors (ZnPP and SnPP).5, 11 On the basis of these findings, Nrf2 activation and HO-1 expression are indicated as redox homeostasis factors, as well as pro-inflammatory factors in IL-1β/NLRP3 inflammasome activation.

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  1. Department of Food Science and Biotechnology, National Chung Hsing University, 145 Xingda Road, Taichung, 40227, Taiwan, China

    Jhih-Jia Jhang & Gow-Chin Yen

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Correspondence to Gow-Chin Yen.

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Jhang, JJ., Yen, GC. The role of Nrf2 in NLRP3 inflammasome activation. Cell Mol Immunol 14, 1011–1012 (2017). https://doi.org/10.1038/cmi.2017.114

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