The role of uric acid as an endogenous danger signal in immunity and inflammation

Abstract

Gout is an ancient disease that still plagues us. Its pathogenic culprit, uric acid crystal deposition in tissues, is a strong inflammatory stimulant. In recent years, the mechanisms through which uric acid crystals promote inflammation have been a subject of increasing interest among rheumatologists and immunologists. Uric acid has been identified as an endogenous adjuvant that drives immune responses in the absence of microbial stimulation. Because uric acid is a ubiquitous metabolite that is produced in high quantities upon cellular injury, the ramifications of its effects may be considerable in health and in disease. Uric acid crystals also have been shown to trigger interleukin-1β-mediated inflammation via activation of the NOD-like receptor protein (NLRP)3 inflammasome, a multimolecular complex whose activation appears to be central to many pathological inflammatory conditions. In this article, we review the possible mechanisms of uric acid-mediated inflammation and offer some historical perspectives on what has been learned about the complex effects of a relatively simple substance.

Fig. 1

Proposed pathways of monosodium urate (MSU)-mediated cellular activation. Uric acid released from injured cells forms MSU crystals upon binding by uric acid–binding antibodies. The crystals convert the complement components via both the classical and the alternative pathways to produce C3a and C5a, as well as membrane attack complexes (MACs). Upon engaging the plasma membrane, MSU interacts with protein receptors Toll-like receptor (TLR)2/4 and CD14, and likely triggers the MyD88/TRIF pathway that leads to nuclear factor-κB (NF-κB) activation. This chain of events may control the activation of antigen-presenting cells (APCs), as well as other proinflammatory cytokine production, with the exception of interleukin (IL)-1β and IL-18. MSU crystals may also bind to cholesterol and trigger lipid sorting, which leads to Syk recruitment by immunoreceptor tyrosine-based activation motif (ITAM)-containing receptors (eg, CD16 and CD32) enriched in the lipid rafts. Syk then turns on phosphatidylinositol 3-kinase (PI3K)-mediated inflammatory phagocytosis. The interaction by MSU with CD16 may be independent of the lipid sorting process. The phagocytosed MSU crystals cause phagolysosomal membrane damage, and cathepsin B released from these vesicles triggers NOD-like receptor protein (NLRP)3 inflammasome activation via a yet-unidentified pathway. This pathway controls the IL-1β production and may be responsible for the systemic inflammation. Question marks indicate suspected links. ROS—reactive oxygen species