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Theranostics 2020; 10(26):12189-12203. doi:10.7150/thno.48028 This issue Cite

Research Paper

IL-33/ST2 induces neutrophil-dependent reactive oxygen species production and mediates gout pain

Chengyu Yin^1#, Boyu Liu^1#, Yuanyuan Li¹, Xiaojie Li¹, Jie Wang¹, Ruixiang Chen¹, Yan Tai², Qiyang Shou³, Ping Wang⁴, Xiaomei Shao¹, Yi Liang¹, Hong Zhou⁵, Wenli Mi⁶, Jianqiao Fang^1✉, Boyi Liu^1✉

1. Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Hangzhou, 310053, China.
2. Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
3. The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou 310053, China.
4. Department of Pathology, School of Basic Medical Science, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
5. Department of Immunology, Anhui Medical University, Hefei, 230032, China.
6. Department of Integrative Medicine and Neurobiology, The Academy of Integrative Medicine, School of Basic Medical Sciences, Institutes of Brain Science, Brain Science Collaborative Innovation Center, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, 200032, China.
#These authors contributed equally to this work.

✉ Corresponding authors: Boyi Liu, Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Hangzhou, 310053, China. E-mail: boyi.liuedu.cn or Jianqiao Fang, Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Hangzhou, 310053, China. E-mail: fangjianqiao7532com. More

Abstract

Objective: Gout, induced by monosodium urate (MSU) crystal deposition in joint tissues, provokes severe pain and impacts life quality of patients. However, the mechanisms underlying gout pain are still incompletely understood.

Methods: We established a mouse gout model by intra-articularly injection of MSU crystals into the ankle joint of wild type and genetic knockout mice. RNA-Sequencing, in vivo molecular imaging, Ca²⁺ imaging, reactive oxygen species (ROS) generation, neutrophil influx and nocifensive behavioral assays, etc. were used.

Results: We found interleukin-33 (IL-33) was among the top up-regulated cytokines in the inflamed ankle. Neutralizing or genetic deletion of IL-33 or its receptor ST2 (suppression of tumorigenicity) significantly ameliorated pain hypersensitivities and inflammation. Mechanistically, IL-33 was largely released from infiltrated macrophages in inflamed ankle upon MSU stimulation. IL-33 promoted neutrophil influx and triggered neutrophil-dependent ROS production via ST2 during gout, which in turn, activated transient receptor potential ankyrin 1 (TRPA1) channel in dorsal root ganglion (DRG) neurons and produced nociception. Further, TRPA1 channel activity was significantly enhanced in DRG neurons that innervate the inflamed ankle via ST2 dependent mechanism, which results in exaggerated nociceptive response to endogenous ROS products during gout.

Conclusions: We demonstrated a previous unidentified role of IL-33/ST2 in mediating pain hypersensitivity and inflammation in a mouse gout model through promoting neutrophil-dependent ROS production and TRPA1 channel activation. Targeting IL-33/ST2 may represent a novel therapeutic approach to ameliorate gout pain and inflammation.

Keywords: Gout, arthritis, TRPA1, reactive oxygen species, cytokine, neutrophil

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