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

• Published in: Cellular & molecular immunology 2015-07, Vol.12 (4), p.424-434
• Main Authors: Jhang, Jhih-Jia, Cheng, Yu-Ting, Ho, Cheng-Ying, Yen, Gow-Chin
• Format: Article
• Language: English
• Subjects: Acetic acid; Antibodies; Antioxidants; Arthritis; Biomedical and Life Sciences; Biomedicine; Carrier Proteins - immunology; Cell Line, Tumor; Crystals; Glutathione; Gout - chemically induced; Gout - immunology; Gout - pathology; Heme; Heme oxygenase (decyclizing); Heme Oxygenase-1 - immunology; Homeostasis; Humans; IL-1β; Immunology; Inflammasomes; Inflammation - chemically induced; Inflammation - immunology; Inflammation - pathology; Inflammatory diseases; Interleukin-1beta - immunology; Joint diseases; Lysosomes - immunology; Medical Microbiology; Microbiology; Monocytes; NF-E2-Related Factor 2 - immunology; NLR Family, Pyrin Domain-Containing 3 Protein; Nuclear transport; Oligomerization; Oxidation-Reduction - drug effects; Oxidative stress; Oxygenase; Phorbol 12-myristate 13-acetate; Protoporphyrin; Protoporphyrin IX; Protoporphyrins - immunology; Pyrin protein; Reactive oxygen species; Reactive Oxygen Species - immunology; research-article; Signal transduction; Signal Transduction - drug effects; Signal Transduction - immunology; Superoxide anions; Tetradecanoylphorbol Acetate - toxicity; Uric acid; Uric Acid - toxicity; Vaccine; 尿酸; 氧化应激反应; 炎症反应; 白细胞介素-1; 结晶; 血红素加氧酶-1; 触发
• ISSN: 1672-7681; 2042-0226
• DOI: 10.1038/cmi.2014.65

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-lβ （IL-lβ） secretion. Reactive oxygen species （ROS） are major mediators of the NLRP3/IL-lβ 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-lβ secretion and NLRP3 inflammasome activation were inhibited by the knockdown of Nrf2 and via the HO-1 inhibitor zinc （11） 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.