Alpha-1 Antitrypsin Mediates Spontaneous Resolution of Acute Gouty Inflammation Via Inhibiting Caspase 3/GSDME-dependent Macrophage Pyroptosis

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.