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

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 (), Chuan Wang () and Boyi Liu ()
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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

Nature Communications, 2024, vol. 15, issue 1, 1-21

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-47640-7

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