Role of citrullination in pyroptotic cell death and rheumatoid arthritis

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Rheumatoid arthritis (RA) is the most prevalent inflammatory rheumatic disease characterized by an immune reaction against joints, extraarticular tissues and other organs. Plasma concentrations of the highly proinflammatory cytokine IL-1ß correlate with RA disease activity and inflammasomes control its release. Inflammasomes have been implicated in RA, since polymorphisms of inflammasome components are associated with disease severity and response to treatment. However, existing data on inflammasomes in RA is limited to gene expression and association studies but no data exist, whether inflammasomes are formed within the lungs, joints and/or released into the circulation of RA patients. Moreover, there is no data, which particular inflammasome is activated in RA and how inflammasomes are implicated in this disease. Moreover, whether there is a role for extracellular inflammasome complexes of the inflammasome adaptor protein ASC, termed ASC specks, that can propagate inflammation, is unknown. We have shown experimentally that autoantibodies to ASC specks enhanced an inflammatory reaction when ASC specks were taken up by other cells. Our preliminary data suggest that ASC specks are citrullinated when inflammasomes are activated and we identified citrullinated ASC specks in the joints of RA patients. Citrullination is a post-translational modification catalyzed by calcium dependent peptidyl-arginine deiminase family enzymes (PADs) into non-essential citrulline amino acids Anti-citrullinated autoantibodies proteins (ACPA) are a hallmark in RA. Our preliminary data further suggest that protein citrullination is common following inflammasome activation in murine and human macrophages and PAD enzyme inhibition results in a dose-dependent reduction in the release of active caspase-1 and IL-1ß from macrophages. We therefore want to study the biochemical connection between inflammasome activation and protein citrullination on a molecular level. Further, we want to address the question whether inflammasome activation is important for the initiation and progression of arthritis, will make use of the CIA and tgTNF-alpha mouse model of RA to study inflammasome activation and investigate the effect of inflammasome inhibition in the context of disease progression in these experimental models.