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CXCL5 activates CXCR2 in nociceptive sensory neurons to drive joint pain and inflammation in experimental gouty arthritis

Author

Listed:
  • Chengyu Yin

    (Zhejiang Chinese Medical University)

  • Boyu Liu

    (Zhejiang Chinese Medical University)

  • Zishan Dong

    (Hebei Medical University)

  • Sai Shi

    (Tianjin University)

  • Chenxing Peng

    (the Second Hospital of Hebei Medical University)

  • Yushuang Pan

    (Zhejiang Chinese Medical University)

  • Xiaochen Bi

    (Zhejiang Chinese Medical University)

  • Huimin Nie

    (Zhejiang Chinese Medical University)

  • Yunwen Zhang

    (Zhejiang Chinese Medical University)

  • Yan Tai

    (Zhejiang Chinese Medical University)

  • Qimiao Hu

    (Zhejiang Chinese Medical University)

  • Xuan Wang

    (The Second Hospital of Hebei Medical University)

  • Xiaomei Shao

    (Zhejiang Chinese Medical University)

  • Hailong An

    (Hebei University of Technology)

  • Jianqiao Fang

    (Zhejiang Chinese Medical University)

  • Chuan Wang

    (Hebei Medical University)

  • Boyi Liu

    (Zhejiang Chinese Medical University)

Abstract

Gouty arthritis evokes joint pain and inflammation. Mechanisms driving gout pain and inflammation remain incompletely understood. Here we show that CXCL5 activates CXCR2 expressed on nociceptive sensory neurons to drive gout pain and inflammation. CXCL5 expression was increased in ankle joints of gout arthritis model mice, whereas CXCR2 showed expression in joint-innervating sensory neurons. CXCL5 activates CXCR2 expressed on nociceptive sensory neurons to trigger TRPA1 activation, resulting in hyperexcitability and pain. Neuronal CXCR2 coordinates with neutrophilic CXCR2 to contribute to CXCL5-induced neutrophil chemotaxis via triggering CGRP- and substance P-mediated vasodilation and plasma extravasation. Neuronal Cxcr2 deletion ameliorates joint pain, neutrophil infiltration and gait impairment in model mice. We confirmed CXCR2 expression in human dorsal root ganglion neurons and CXCL5 level upregulation in serum from male patients with gouty arthritis. Our study demonstrates CXCL5-neuronal CXCR2-TRPA1 axis contributes to gouty arthritis pain, neutrophil influx and inflammation that expands our knowledge of immunomodulation capability of nociceptive sensory neurons.

Suggested Citation

  • Chengyu Yin & Boyu Liu & Zishan Dong & Sai Shi & Chenxing Peng & Yushuang Pan & Xiaochen Bi & Huimin Nie & Yunwen Zhang & Yan Tai & Qimiao Hu & Xuan Wang & Xiaomei Shao & Hailong An & Jianqiao Fang & , 2024. "CXCL5 activates CXCR2 in nociceptive sensory neurons to drive joint pain and inflammation in experimental gouty arthritis," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47640-7
    DOI: 10.1038/s41467-024-47640-7
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    References listed on IDEAS

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    1. Alia M. Obeidat & Matthew J. Wood & Natalie S. Adamczyk & Shingo Ishihara & Jun Li & Lai Wang & Dongjun Ren & David A. Bennett & Richard J. Miller & Anne-Marie Malfait & Rachel E. Miller, 2023. "Piezo2 expressing nociceptors mediate mechanical sensitization in experimental osteoarthritis," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    2. Anya Topiwala & Kulveer Mankia & Steven Bell & Alastair Webb & Klaus P. Ebmeier & Isobel Howard & Chaoyue Wang & Fidel Alfaro-Almagro & Karla Miller & Stephen Burgess & Stephen Smith & Thomas E. Nicho, 2023. "Association of gout with brain reserve and vulnerability to neurodegenerative disease," Nature Communications, Nature, vol. 14(1), pages 1-9, December.
    3. Jianhua Zhao & John V. Lin King & Candice E. Paulsen & Yifan Cheng & David Julius, 2020. "Irritant-evoked activation and calcium modulation of the TRPA1 receptor," Nature, Nature, vol. 585(7823), pages 141-145, September.
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