ALDH2 Ameliorates Acute Gouty Arthritis Through Inhibiting NLRP3 Inflammasome and Pyroptosis by Nrf2/ROS Pathway

Background: Gouty arthritis is a common disease characterized by the deposition of monosodium urate (MSU) crystals in joint and non-joint structures. Nonetheless, the role of aldehyde dehydrogenase 2 (ALDH2) in the pathophysiology of acute gout remains unclear. This study aimed to evaluate the role of ALDH2 in MSU crystal-induced acute gout attacks and related mechanisms and to identify potential therapeutic strategies for gout management.

Methods: Peripheral blood mononuclear cells (PBMCs) from gout patients and healthy controls were isolated via Ficoll-Paque Plus density gradient centrifugation. A mouse model of gouty arthritis was established by injecting MSU crystal suspension into the foot pad. In vitro, PMA-differentiated THP-1 cells were stimulated with MSU crystals. We then investigated the effect of the ALDH2 Agonist Alda-1 on MSU crystal-induced acute inflammation. Furthermore, the Nrf2 inhibitor ML385 was used to define the Nrf2 pathway's role in mediating ALDH2 activation effects during acute gout attacks.

Results: We found that compared to healthy controls, ALDH2 expression was significantly decreased in the PBMCs of patients with acute gout and negatively correlated with C-reactive protein levels. In mice models with acute gout, treatment with Alda-1 effectively mitigated MSU-induced footpad edema, along with reductions in inflammatory cell infiltration and pro-inflammatory cytokine production in the local tissue of the footpad. In vitro studies demonstrated that Alda-1 significantly reduced oxidative stress induced by MSU crystal stimulation and suppressed the activation and assembly of the NLRP3 inflammasome, as well as the resulting Pyroptosis. Further experiments revealed that Alda-1 treatment promoted Nrf2 nuclear translocation, alleviating oxidative stress and cellular inflammation.

Conclusion: Our findings suggest that Alda-1-mediated activation of ALDH2 can alleviate MSU-induced oxidative stress and inflammation by regulating the Nrf2/ROS pathway and may represent a promising therapeutic strategy for managing acute gouty arthritis.