Tissue-Resident Macrophage PIEZO1 Transduces Mechanical Stress into Inflammatory Pain in Acute Gout

Neurosci Bull. 2026 Mar 6. doi: 10.1007/s12264-026-01592-8. Online ahead of print.

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.

PMID:41790423 | DOI:10.1007/s12264-026-01592-8