Mechanisms of inflammation in gout

Abstract

An acute attack of gout is a paradigm of acute sterile inflammation, as opposed to pyogenic inflammation. Recent studies suggest that the triggering of IL-1beta release from leucocytes lies at the heart of a cascade of processes that involves multiple cytokines and mediators. The NLRP3 inflammasome appears to have a specific role in this regard, but the biochemical events leading to its activation are still not well understood. We review the known mechanisms that underlie the inflammatory process triggered by urate crystals and suggest areas that require further research.

Figure 1

Composition of the NALP3 inflammasome and its activation by monosodium urate. Phagocytosis of monosodium urate (MSU) crystals leads to the generation of reactive oxygen species (ROS) through activation of NADPH oxidases. This event activates the NLRP3 inflammasome. MSU crystals may also induce the secretion of ATP, which in turn activates P2X7R. On activation of the P2X7 receptor, there is rapid exit of intracellular potassium that triggers the NLRP3 inflammasome. A rise in intracellular calcium is also required for the secretion of processed IL-1β. The macromolecular complex (inflammasome) consists of NLRP3, ASC and procaspase-1, and CARDINAL. Assembly leads to activation of caspase-1, which in turn cleaves pro-IL-1β to produce biologically active IL-1β. ASC, apoptosis-associated speck-like protein containing a caspase recruitment domain (CARD); FIIND, domain with function to find; LRR, leucine-rich repeat; MDP, muramyl dipeptide; NACHT, domain conserved in NAIP, CIITA, HET-E and TP1; NALP3, NACHT-containing, LRR-containing and PYD-containing protein; PYD, pyrin death domain.

Figure 2

Multiple steps are needed to trigger inflammation in gout. (1) Recognition of monosodium urate (MSU) crystals by components of the innate immune system - Toll-like receptor (TLR) 2/TLR4, triggering receptor expressed on myeloid cells (TREM), and so forth. (2) Uptake of MSU by phagocytotic cells (for example, macrophages and eventually mast cells). (3) Activation of the NALP3 inflammasome by MSU (see details in Figure 1). (4) Release of IL-1β from the cell. (5) Endothelial IL-1β receptor type 1 (IL-1R) activation. (6) Proinflammatory mediators, including IL-8, release a potent chemokine for neutrophil recruitment. (7) Neutrophil recruitment into the site of inflammation. (8) Release of proinflamatory compounds by neutrophils, including more IL-1β.