Negative regulation of the NLRP3 inflammasome by A20 protects against arthritis

Abstract

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 diseases1, 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 (A20myel-KO mice) triggers a spontaneous erosive polyarthritis that resembles RA in patients2. Notably, RA in A20myel-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 A20myel-KO mice. These results reveal A20 as a novel negative regulator of Nlrp3 inflammasome activation, and describe A20myel-KO mice as the first experimental model to study the role of inflammasomes in RA pathology.

A20 inhibition of STAT1 expression in myeloid cells: a novel endogenous regulatory mechanism preventing development of enthesitis

“…The generation and phenotypical characterisation of A20 myelKO mice were previously described 5 6. Detailed information on these mice can be found in the online supplementary data.…”

“…Here, we focused on mice with a myeloid cell-specific A20 deficiency, referred to as A20 myelKO mice. The inflammation in these mice is dependent on Nlrp3 inflammasome activation, interleukin (IL)-6 and IL-1 receptor signalling, but independent of TNF 5 6…”

Autoinflammatory diseases: update on classification diagnosis and management

“…Altogether, this leads to a strong proinflammatory state, which was illustrated by significantly increased levels of proinflammatory cytokines (IL-1β, TNF, IL-6, IL-18 and IL-17) in patients' sera and also in supernatant from patient-derived PBMCs stimulated with Lipopolysaccharide (LPS). Another potential effect of A20 haploinsufficiency was suggested by a murine study18 19 that demonstrated a negative effect of this protein on NLRP3 inflammasome activation and this was independent of A20's effect on NF-κB regulation. Interestingly, constitutive activation of the NLRP3 inflammasome was also demonstrated in patient-derived PBMCs, and the fact that anti-IL-1 inhibition was used successfully in one patient, although at a very high dose, supports the notion that NLRP3 inflammasome dysregulation is one of the consequences of A20 haploinsufficiency.…”

Investigation of Candidate Gene Polymorphisms in an Immune Response as Markers for the Risk of Developing Rheumatoid Arthritis and Producing Autoantibodies

“…У мышей специфическая абляция гена tnfaip3 из миелоидных клеток приводила к развитию тяжелого по-лиартрита, подобного РА у человека [42]. Недавно на этой же мышиной модели также было показано, что белок А20 является негативным регулятором Nlrp3 (NOD-like receptor family, pyrin domain containing 3) инфламмасомной ак-тивации [43]. В последние годы выявлено, что система NLRP3 играет значительную роль в патогенезе иммуно-воспалительных, в том числе аутовоспалительных, заболе-ваний человека [44][45][46].…”