Figure 1. Mechanisms of inflammation and interleukin-1 (IL-1) antagonism in acute gout. In acute gout, phagocytosed monosodium urate monohydrate (MSU) crystals activate the NLRP3 inflammasome, leading to caspase 1 activation, which in turn leads to cleavage of proIL-1β and secretion of mature IL-1β. IL-1β can induce further production of IL-1β (as well as many other mediators of inflammation) and further activation of synovial lining cells and phagocytes. MSU crystals also induce many other inflammatory cytokines (e.g., tumor necrosis factor α [TNFα], IL-6, IL-8, and alarmins such as S100A8/A9) by both IL-1–dependent and IL-1–independent mechanisms, and MSU crystal–induced C5b–9 terminal complement pathway activation is an important driver of experimental acute gout. IL-1β must bind to both IL-1 receptor type I (IL-1R1) and IL-1 receptor accessory protein (IL-1RAcP) for signal transduction to occur. In endothelial cells, IL-1β appears to be a major trigger for altered adhesion molecule and chemokine expression, which, together with the other inflammatory events, results in neutrophil recruitment that drives the initiation of gouty inflammation. IL-1α, which is not depicted here, is expressed as a plasma membrane–bound molecule that also binds the IL-1 receptor. The role of IL-1α in experimental and clinical gout has not yet been defined via direct study. Anakinra binds to IL-1R1, blocking IL-1β and IL-1α; rilonacept acts as a soluble receptor, comprising both IL-1R1 and IL-1RAcP fused to the Fc portion of IgG1, neutralizing IL-1β as well as IL-1α; and canakinumab, a monoclonal antibody with IL-1β specificity, neutralizes IL-1β only.Download figure to PowerPoint