Uric acid drives intestinal barrier dysfunction through TSPO-mediated NLRP3 inflammasome activation
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Inflammation Research
ORIGINAL RESEARCH PAPER
Uric acid drives intestinal barrier dysfunction through TSPO‑mediated NLRP3 inflammasome activation Qiulan Lv1 · Daxing Xu1 · Jinfeng Ma1 · Yan Wang1 · Xiaomin Yang1 · Peng Zhao1 · Liang Ma1 · Zhiyuan Li1 · Wan Yang1 · Xiu Liu1 · Guanpin Yang2 · Shichao Xing1,3 Received: 12 July 2020 / Revised: 28 September 2020 / Accepted: 1 October 2020 © Springer Nature Switzerland AG 2020
Abstract Background and aim Intestinal epithelial dysfunction is the foundation of various intestinal and extra-intestinal diseases, while the effects and mechanism of uric acid on the intestinal barrier are little known. TSPO has been shown to be related to the generation of ROS and is involved in regulating inflammation, whether uric acid drives intestinal epithelial dysfunction through TSPO-mediated NLRP3 inflammasome activation is unknown. Methods UOX gene knockout mouse (UOX-/-) were used for models of hyperuricemia. Fluorescein isothiocyanate (FITC)labeled dextran was used to assess in vivo intestinal permeability. Serum lipopolysaccharide (LPS) and culture supernatants IL-1β were measured using ELISA Kit. IEC-6 exposed to different concentrations of uric acid was used for in vitro experiment. Protein content and mRNA were assessed using Western blotting and Q-PCR, respectively. Intracellular ROS was determined using flow cytometry and fluorescence microscope. Mitochondrial membrane potential was detected on an immunofluorescence. Small interfering RNA transfection was used to assess the interaction between translocator protein (TSPO) and NLRP3 inflammasome. N-acetyl-L-cysteine (NAC) was used as ROS scavenger. Results Our results showed that hyperuricemia mice were characteristic by increased intestinal permeability. Hyperuricemia upregulated TSPO, increased production of ROS and activated NLRP3 inflammasome, which resulted in lower expression of occludin and claudin-1. In vitro, we showed that soluble uric acid alone increased the expression of TSPO, depolarized mitochondrial membrane potential, increased ROS release and activated NLRP3 inflammasome, which further reduced the expression of occludin and claudin-1. Silencing TSPO suppressed NLRP3 inflammasome activation and increased expression of claudin-1 and occludin, which was accompanied by lower levels of ROS. Scavenging ROS also significantly inhibited NLRP3 inflammasome activation without change of TSPO, indicating that TSPO-mediated NLRP3 inflammasome activation was dependent on ROS. Conclusions In conclusion, uric acid drives intestinal barrier dysfunction through TSPO-mediated NLRP3 inflammasome. Keywords Uric acid · Intestinal epithelial barrier · TSPO · NLRP3 inflammasome
Introduction Qiulan Lv and Daxing Xu contributed equally to this work. * Shichao Xing [email protected] 1
Medical Research Center, Affiliated Hospital of Qingdao University, No. 167, Wutai Mountain Road, Qingdao 266003, People’s Republic of China
2
The Key Laboratory of Mariculture of Chinese Ministry of Education, Ocean University of Chin
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