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Monosodium urate crystals trigger Nrf2- and heme oxygenase-1-dependent inflammation in THP-1 cells

Cellular & Molecular Immunology volume 12, pages 424–434 (2015)Cite this article

Abstract

Gouty arthritis is an inflammatory disease that is caused by an accumulation of monosodium urate (MSU) crystals in the joints. MSU is capable of activating the nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3 (NLRP3) inflammasome, leading to interleukin-1β (IL-1β) secretion. Reactive oxygen species (ROS) are major mediators of the NLRP3/IL-1β interaction. Although nuclear factor E2-related factor 2 (Nrf2) is recognized as a transcription factor that is involved in the response to oxidative stress, the effect of MSU on Nrf2 and on Nrf2-mediated antioxidant enzymes remains unclear. The treatment of THP-1 monocytes using phorbol 12-myristate 13-acetate (PMA) was shown to initiate inflammatory responses. Here, we showed that THP-1 cells, following treatment with MSU crystals, significantly increased IL-1β release, NLRP3 inflammasome activation and ROS production. MSU also promoted the nuclear translocation of Nrf2 and activated lysosomal destabilization. Moreover, the levels of heme oxygenase-1 (HO-1) in gene and protein expressions were upregulated by MSU. MSU-induced IL-1β secretion and NLRP3 inflammasome activation were inhibited by the knockdown of Nrf2 and via the HO-1 inhibitor zinc (II) protoporphyrin IX (ZnPP). In addition, HO-1 inhibition increased the level of superoxide anion production and the consumption of glutathione. These findings suggest that Nrf2 and HO-1 mediate redox homeostasis and interact with pro-inflammatory factors in MSU-challenged THP-1 cells, thereby providing new insight into how MSU-induced gouty inflammation is mediated by specific mechanisms that are involved in the Nrf2/Ho-1 antioxidant signaling pathway.

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Acknowledgements

This research work was supported in part by the National Science Council, NSC102-2313-B-005-006-MY3, Taiwan, and by the Ministry of Education, Taiwan, under the ATU plan.

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Authors and Affiliations

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

    Jhih-Jia Jhang, Yu-Ting Cheng, Cheng-Ying Ho & Gow-Chin Yen

  2. Agricultural Biotechnology Center, National Chung Hsing University, Taichung, Taiwan, China

    Gow-Chin Yen

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  1. Jhih-Jia Jhang
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Correspondence to Gow-Chin Yen.

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Supplementary Information accompanies the paper on Cellular & Molecular Immunology's website (http://www.nature.com/cmi).

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Jhang, JJ., Cheng, YT., Ho, CY. et al. Monosodium urate crystals trigger Nrf2- and heme oxygenase-1-dependent inflammation in THP-1 cells. Cell Mol Immunol 12, 424–434 (2015). https://doi.org/10.1038/cmi.2014.65

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