Tianyi Shen1,2  · Ting Wang1,2  · Liyan Wu1,2  · Zihan Wang1,2 · Liqin Gan3  · Yubin Luo4  · Cong Liu5  · Yang Xu6  · De‑An Guo2,3 · Qirui Bi3  · Wanying Wu2,3 · Lvyi Chen7  · Yi Chang8  · Jing Feng1,2

1 State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Science, Shanghai 201203, China 

2 University of Chinese Academy of Sciences, Beijing 100049, China 

3 Shanghai Research Center for Modernization of Traditional Chinese Medicine, National Engineering Laboratory for TCM Standardization Technology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China 

4 Department of Rheumatology and Immunology, Laboratory of Rheumatology and Immunology, Frontiers Science Center for Disease‑related Molecular Network, West China Hospital, Sichuan University, Chengdu 610064, China 

5 International Cooperation Base for Active Substances in Traditional Chinese Medicine in Hubei Province, School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan 430074, China 

6 Department of Orthopedics, West China Hospital, Sichuan University, Chengdu 610041, China 

7 School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan 430074, China 

8 Yangpu Hospital, School of Medicine, Tongji University, Shanghai 200092, China

Abstract

Gouty arthritis is an autoinflammatory joint disease caused by the deposition of monosodium urate crystals, which activate innate immune responses and elicit acute episodes of joint pain and inflammation. Although macrophages are key players in recognizing monosodium urate (MSU) crystals and initiating the inflammatory cascade, the specific contribution of tissue-resident macrophages and their mechanosensory machinery remains unclear. Here, we identify the mechanosensitive ion channel PIEZO1 as a critical mediator of inflammation and pain in MSU-induced acute gout. We show that synovial CX3CR1⁺ tissue-resident macrophages are enriched and activated in both patient samples and a murine model of gout. PIEZO1 is highly expressed in these cells and responds to mechanical stress with calcium influx, which is further amplified in MSU-treated joints. Pharmacological inhibition or genetic ablation of PIEZO1 in CX3CR1⁺ macrophages significantly attenuated joint swelling, inflammatory cytokine expression, mechanical hypersensitivity, and motor dysfunction. In contrast, Piezo1 deletion in CCR2⁺ monocytes, MRP8⁺ neutrophils, or Col1a2⁺ fibroblasts did not affect gout-associated symptoms, indicating a non-redundant role for resident macrophage-expressed PIEZO1. These findings define a PIEZO1-dependent mechanotransduction pathway in tissue-resident macrophages that drives gout-related inflammation and nociception and suggest that targeting PIEZO1 may offer therapeutic benefit in acute gout flares.

Keywords

PIEZO1; Gouty arthritis; Tissue-resident macrophage; IL-1β

[SpringerLink]