Alpha-1 Antitrypsin Mediates Spontaneous Resolution of Acute Gouty Inflammation Via Inhibiting Caspase...

Research on spontaneous resolution of acute gout remains limited. Macrophages pyroptosis is crucial for the inflammation of acute gout, while current research mainly focus on Caspase 1/Gasdermin D axis. We aimed to investigate the involvement of other Gasdermin proteins in MSU crystal-induced macrophages, and to explore the role of Caspase 3-interacting protein alpha-1 antitrypsin (AAT) in regulating macrophage pyroptosis. Here, clinical evidence demonstrated elevated Gasdermin E (GSDME) in peripheral blood mononuclear cells (PBMCs) and CD68⁺ synovial macrophages from patients with acute gout. In THP-1-derived macrophages, activated Caspase 3/GSDME axis was found after MSU crystals stimulation, and knockdown of Caspase 3 and GSDME significantly suppressed pyroptosis. In vivo, the Caspase 3 inhibitor effectively alleviated MSU crystal-induced acute gouty arthritis in mice. Cytologically, Caspase 3 interacting protein AAT was identified using immunoprecipitation and mass spectrometry technology. Meanwhile, AAT was elevated in serum, PBMCs, synovial fluids, and CD68⁺ synovial macrophages from patients with acute gout. Furthermore, AAT inhibited Caspase 3/GSDME-dependent pyroptosis axis by binding to Caspase 3 in MSU crystal-induced macrophages. Additionally, AAT was internalized into macrophages via low-density lipoprotein receptor-related protein-1. Collectively, elevated AAT in synovial fluids from patients with acute gout attenuates macrophage pyroptosis by inhibiting Caspase 3/GSDME axis, providing a novel explanation for the spontaneous resolution of acute gout.