Figure 1

The innate immune response in recognition, uptake, and responses of cells to monosodium urate (MSU) crystals. As discussed in the text, recognition of the naked MSU crystal by the toll-like receptors 2 and 4 (TLR2, TLR4), which are normally involved in triggering innate host defense responses to infectious pathogens is a primary trigger of inflammatory and degenerative tissue reactions associated with gouty arthritis. TLR2, TLR4, and the TLR adaptor protein MyD88 promote ingestion of the naked MSU crystal by phagocytes. Downstream of TLR2 and TLR4 recognition of the MSU crystal, MyD88 transduces activation of the transcription factor NF-κB and the expression of a variety of pro-inflammatory mediators. Intracellular assembly of the cytosolic NALP3 (cryopyrin) inflammasome protein complex is subsequently triggered by delivery to the inflamamsome of ingested MSU crystals in phagocytes. The inflammasome assembly in response to MSU crystals triggers caspase-1 activation and the maturation and release of IL-1β in phagocytes. MSU crystal-induced (but not ATP-induced) NALP3 inflammasome protein complex assembly is suppressed by high concentrations of the microtubule inhibitor colchicine, suggesting that a high concentration of colchicine blocks delivery of the crystals to the NALP3 inflammasome AP, activator protein; iNOS, inducible nitric oxide synthase; MMP, matrix metalloproteinase.