Mechanisms of inflammation in gout

The clinical manifestations of gout are due to interactions between monosodium urate (MSU) crystals and local tissues. This review article outlines recent advances in the understanding of the mechanisms of inflammation in gout. We focus on the cellular response to MSU crystals during acute arthritis, termination of the acute attack and maintenance of asymptomatic hyperuricaemia, and chronic tophaceous disease. We then propose a unifying model of gout involving the differential role of mononuclear phagocytes in the regulation of the inflammatory response to MSU crystals. The acute attack of gout has all the hallmarks of an acute inflammatory response. Histological examination of the synovium in acute gout shows lining layer hyperplasia and intense infiltration of the membrane by neutrophils, mononuclear phagocytes and lymphocytes [1, 2]. Acute attacks of gout are often triggered by specific events, such as trauma, surgery, intercurrent illness, excess alcohol intake or drugs that alter serum urate levels. Such events may stimulate de novo formation of MSU crystals or may trigger release of microcrystals from preformed deposits within the joint. Although supersaturation of interstitial fluid with MSU is required for the development of crystals, other factors, such as local temperature and pH within the joint, also influence whether crystal formation occurs [3]. Debris within the synovial cavity may provide an initial nucleus for early crystal development [4]. In addition, MSU crystal nucleation may be stabilized by albumin and by immunoglobulin [5, 6]. Depletion of endogenous mast cells has been found to significantly inhibit neutrophil influx in the murine MSU crystal-induced peritonitis model, suggesting a role for crystal-induced mast cell degranulation in initiating inflammation [7]. Mast cells contain preformed proinflammatory substances, including histamine, cytokines [including tumour necrosis factor α (TNF-α)] and enzymes such as tryptase, mast cell chymase and serine esterases, all of which may contribute to the promotion of downstream inflammatory cascades.