TRPM7 inhibition alleviates acute gouty arthritis in mice by suppressing M1 polarization through the EDN1/EDNRB axis.

Abstract

Gouty arthritis (GA) is caused by the deposition of urate crystals in joints, which elicits a robust inflammatory response in articular and periarticular tissues. However, effective therapeutic strategies remain limited. Transient receptor potential melastatin 7 (TRPM7) is a cation channel widely expressed in innate immune cells such as macrophages and neutrophils, exerts a pivotal role in the innate immune system by mediating intracellular Cainflux to regulate the functions of these cells. This study aimed to investigate the mechanism and therapeutic potential of TRPM7 in MSU-induced macrophage M1 polarization during GA. We performed genetic Trpm7 deletion using Trpm7Lysm-Cre mice, and utilized the TRPM7 inhibitor 2-APB to investigate the role of TRPM7 in macrophage M1 polarization induced by MSU crystals. RNA-seq analysis revealed the downstream molecules of TRPM7 in macrophage polarization. Our study showed that TRPM7 was abnormally upregulated in the synovial tissues of acute gouty arthritis (AGA) model mice. Pharmacological inhibition of TRPM7 mitigates M1 polarization, oxidative stress, and inflammatory cytokine production in bone marrow-derived macrophages (BMDMs). Mechanistically, TRPM7 promotes M1 phenotypic transition of BMDMs via increasing intracellular Cainflux, which activates the endothelin-1 (EDN1)/endothelin B receptor (EDNRB) signaling axis to amplify pro-inflammatory responses and oxidative stress. Furthermore, treatment with the TRPM7 inhibitor 2-APB significantly alleviates joint swelling and inflammatory infiltration in a murine AGA model. In conclusion, our findings reveal a novel regulatory mechanism involved in the pathogenesis of GA and suggest that targeting TRPM7 may serve as a potential strategy for the prevention and treatment of GA.