TRIM21 Orchestrates Inflammasome Assembly and Drives Autoinflammatory Pathology.

Introduction/Rationale: Inflammasomes are pivotal cytoplasmic scaffolds that drive the maturation of interleukin (IL)-1β and IL-18 and initiate pyroptotic cell death. Tight regulation of inflammasome activity is critical, as uncontrolled IL-1β release underlies chronic inflammation and autoinflammatory disease. The adaptor protein ASC is essential for inflammasome assembly, and its polymerization and extracellular release amplify inflammatory responses. TRIM21, an E3 ubiquitin ligase and common autoantigen in autoimmune diseases, has been implicated in pyroptosis regulation; however, its role in inflammasome assembly and autoinflammatory disease remains unclear. Mechanistic insights into ASC polymerization and particle release are also incomplete.

Methods: We investigated TRIM21’s role in inflammasome activation using TRIM21-deficient human monocytes and bone marrow–derived macrophages from conditional Trim21 knockout mice. Systemic autoinflammation was assessed in murine models of cryopyrin-associated periodic syndrome (CAPS) and familial Mediterranean fever (FMF), and findings were validated in plasma from CAPS patients.

Results: TRIM21 is a conserved and essential mediator of inflammasome assembly. It interacts with, ubiquitinates, and promotes polymerization of ASC, facilitating inflammasome assembly and the release of ASC/TRIM21 particles during pyroptosis in human and mouse macrophages. Notably, systemic ASC/TRIM21 particles and corresponding autoantibodies were detected in both murine and human autoinflammatory disease.

Conclusion: Our findings establish TRIM21 as a critical regulator of inflammasome assembly and particle release, linking it to the pathogenesis of autoinflammatory disease. These results extend TRIM21’s known role in autoimmunity to a previously unrecognized function in driving inflammasome-mediated inflammation, highlighting it as a potential therapeutic target in autoinflammatory disorders.