Arthritides are chronic, progressive systemic inflammatory diseases that lead to significant joint damage, pain, dysfunction, and disability. A20, also known as TNFAIP3, is genetically and epigenetically linked to human arthritis, and recent experimental studies implicate A20 in regulating several potential pathophysiological arthritis pathways. Mice bearing A20 deficient dendritic cells or A20 deficient macrophages/neutrophils spontaneously develop arthritis. A20 restricts several inflammatory pathways, including TLR, TNF?, and inflammasome signals. How A20 performs these critical functions and prevents arthritis are poorly understood. A20 has multiple motifs that mediate deubiquitinating, ubiquitin binding, and E3 ubiqutin ligase activities. The goal of this proposal is to understand the biochemical mechanisms by which A20 prevents arthritis. We have generated several knock-in lines of mice with strategic point mutations that abrogate specific biochemical functions of A20. Using these new mouse strains, we will determine which of A20's ubiquitin dependent functions preserve the cellular and molecular pathways that prevent arthritis. The proposed studies will establish a new robust mouse model of spontaneous arthritis based on a human arthritis susceptibility protein.
Inflammatory arthritides, including rheumatoid arthritis, psoriatic arthritis, spondyloarthritis, et al, are chronic, progressive systemic inflammatory diseases that cause disability for many people. Although new therapeutics have improved outcomes in recent years, few patients are cured and many patients fail current therapies. A20 has been linked to several types of inflammatory arthritis in human genetic studies and experimental models. Thus, our studies investigating how A20 restricts inflammatory pathways are central to finding the underlying causes of and cures for these diseases.
