Negative regulation of the NLRP3 inflammasome by A20 protects against arthritis

Rheumatoid arthritis (RA) is a chronic autoinflammatory disease that affects 1-2% of the world population and is characterized by widespread joint inflammation. IL-1 is an important mediator of cartilage destruction in rheumatic diseases(1), but our understanding of the upstream mechanisms leading to IL-1β production in rheumatoid arthritis is limited by the absence of suitable RA mouse models in which inflammasomes contribute to pathology. Myeloid-cell-specific deletion of the RA-susceptibility gene A20/TNFAIP3 in mice (A20(myel-KO) mice) triggers a spontaneous erosive polyarthritis that resembles RA in patients(2). Notably, RA in A20(myel-KO) mice was not rescued by tumor necrosis factor receptor 1 (TNF-R1) deletion, but we showed it to crucially rely on interleukin-1 receptor (IL-1R) signaling. Macrophages lacking A20 had increased basal and LPS-induced expression levels of the inflammasome adaptor Nlrp3 and proIL-1β. As a result, A20-deficiency in macrophages significantly enhanced Nlrp3 inflammasome-mediated caspase-1 activation, pyroptosis and IL-1β secretion by soluble and crystalline Nlrp3 stimuli. In contrast, activation of the Nlrc4 and AIM2 inflammasomes was not altered. Importantly, increased Nlrp3 inflammasome activation contributed to RA pathology in vivo, because deletion of Nlrp3 and caspase-1 markedly protected against RA-associated inflammation and cartilage destruction in A20(myel-KO) mice. These results reveal A20 as a novel negative regulator of Nlrp3 inflammasome activation, and describe A20(myel-KO) mice as the first experimental model to study the role of inflammasomes in RA pathology.