Fig. 4: Pyroptosis in RA pathogenesis.

RA is characterized by synovitis and cartilage degeneration. Autoimmune components and immune cells are involved in RA. In synovial tissue infiltrating macrophages, NLRP3 is activated by PTX3 and C1q, which is enhanced by IL-6 and regulated by A20. A deficit of mitochondrial gene MRE11A in T cells leads to mtDNA instability and leakage, decreased cytosolic ATP, and activation of NLRP3 and AIM2 inflammasomes, which participate in canonical jointly. Decreased H⁺ in RA synovial fluid promotes the opening of ASIC1a ion channels on chondrocytes and synovial cells, leading to Ca²⁺ influx and activation of NLRP3. In FLSs, the classical pyroptosis pathway is mainly activated by ROS and LPS. LPS also leads to GSDMD cleavage and non-classical pore formation through caspase-3 activation.