Journal
CELLULAR & MOLECULAR IMMUNOLOGY
Volume 12, Issue 4, Pages 424-434Publisher
CHIN SOCIETY IMMUNOLOGY
DOI: 10.1038/cmi.2014.65
Keywords
HO-1; monosodium urate; NLRP3 inflammasome; Nrf2; THP-1 cells
Categories
Funding
- National Science Council, Taiwan [NSC102-2313-B-005-006-MY3]
- Ministry of Education, Taiwan, under the ATU
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Gouty arthritis is an inflammatory disease that is caused by an accumulation of monosodium urate (MSU) crystals in the joints. MSUis capable of activating the nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3 (NLRP3) inflammasome, leading to interleukin-1 beta (IL-1 beta) secretion. Reactive oxygen species (ROS) are major mediators of the NLRP3/IL-1 beta 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-1 beta 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-1 beta 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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